NM_004260.4:c.2395G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004260.4(RECQL4):c.2395G>A(p.Val799Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,598,680 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V799L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 33)

Exomes 𝑓: 0.027 ( 675 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 2.27

Publications

14 publications found

Variant links:

COSMIC-nc: COSV107348431

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

RECQL4 Gene-Disease associations (from GenCC):

Baller-Gerold syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
Rothmund-Thomson syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Rothmund-Thomson syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
osteosarcoma
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
rapadilino syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

RECQL4 links:

ENSG00000265393 (HGNC:):

ENSG00000265393 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010660559).

BP6

Variant 8-144513286-C-T is Benign according to our data. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513286-C-T is described in CliVar as Benign. Clinvar id is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2613/152246) while in subpopulation NFE AF = 0.0282 (1919/67988). AF 95% confidence interval is 0.0272. There are 29 homozygotes in GnomAd4. There are 1211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.2395G>A	p.Val799Met	missense_variant	Exon 14 of 21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 link	c.2395G>A	p.Val799Met	missense_variant	Exon 14 of 21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 link	c.1324G>A	p.Val442Met	missense_variant	Exon 13 of 20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 link	c.633+130G>A		intron_variant	Intron 5 of 7	5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 link	n.272-320C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2612

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0242

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0282

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0162

AC:

3646

AN:

225518

AF XY:

0.0160

show subpopulations

Gnomad AFR exome

AF:

0.00455

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.0259

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0268

AC:

38695

AN:

1446434

Hom.:

675

Cov.:

AF XY:

0.0257

AC XY:

18493

AN XY:

719970

show subpopulations

African (AFR)

AF:

0.00452

AC:

151

AN:

33444

American (AMR)

AF:

0.0113

AC:

505

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00196

AC:

AN:

26034

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39638

South Asian (SAS)

AF:

0.00392

AC:

337

AN:

86008

European-Finnish (FIN)

AF:

0.0230

AC:

918

AN:

39992

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0318

AC:

35344

AN:

1110936

Other (OTH)

AF:

0.0230

AC:

1380

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

2395

4791

7186

9582

11977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1374

2748

4122

5496

6870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0172

AC:

2613

AN:

152246

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1211

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00522

AC:

217

AN:

41562

American (AMR)

AF:

0.0107

AC:

163

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00394

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0242

AC:

257

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0282

AC:

1919

AN:

67988

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

125

250

375

500

625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0222

Hom.:

142

Bravo

AF:

0.0162

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.00537

AC:

ESP6500EA

AF:

0.0226

AC:

186

ExAC

AF:

0.0158

AC:

1883

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 05, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published in association with Rothmund-Thomson syndrome (Wang et al., 2003; Suter et al., 2016). Wang et al. reported that the V799M variant was observed in cis with the P1170L variant in their patient, making V799M's contribution to disease uncertain. Limited information on the patient was available from Suter et al. publication.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27247962, 12734318) -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RECQL4: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

May 19, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rapadilino syndrome

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rothmund-Thomson syndrome type 2

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Baller-Gerold syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Feb 24, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.11

T;D

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.011

T;T

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

2.3

PrimateAI

Uncertain

0.59

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

.;D

Vest4

0.75

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.56

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over