Genetic Variant NM_004260.4:c.3062G>A (chr8-144512318-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5BP6BS1BS2

The NM_004260.4(RECQL4):c.3062G>A(p.Arg1021Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,612,274 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1021P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0041 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0052 ( 24 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10O:1

Conservation

PhyloP100: -0.313

Publications

17 publications found

Variant links:

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, SUPPORTIVE Submitted by: Orphanet, G2P
Rothmund-Thomson syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Rothmund-Thomson syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
osteosarcoma
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
rapadilino syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-144512319-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP6

Variant 8-144512318-C-T is Benign according to our data. Variant chr8-144512318-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135147.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00411 (627/152382) while in subpopulation NFE AF = 0.00682 (464/68044). AF 95% confidence interval is 0.00631. There are 0 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL4	NM_004260.4	MANE Select	c.3062G>A	p.Arg1021Gln	missense	Exon 18 of 21	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.3137G>A	p.Arg1046Gln	missense	Exon 17 of 20	NP_001399948.1
RECQL4	NM_001413036.1		c.3062G>A	p.Arg1021Gln	missense	Exon 18 of 21	NP_001399965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3062G>A	p.Arg1021Gln	missense	Exon 18 of 21	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.1991G>A	p.Arg664Gln	missense	Exon 17 of 20	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.2969G>A	p.Arg990Gln	missense	Exon 18 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

627

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00418

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00682

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00408

AC:

1006

AN:

246782

AF XY:

0.00401

show subpopulations

Gnomad AFR exome

AF:

0.000853

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000280

Gnomad NFE exome

AF:

0.00688

Gnomad OTH exome

AF:

0.00516

GnomAD4 exome

AF:

0.00523

AC:

7640

AN:

1459892

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

3716

AN XY:

726186

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33474

American (AMR)

AF:

0.00340

AC:

152

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00785

AC:

205

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.000510

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000578

AC:

AN:

51934

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00618

AC:

6871

AN:

1111610

Other (OTH)

AF:

0.00472

AC:

285

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

474

948

1423

1897

2371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<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:

0.00411

AC:

627

AN:

152382

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

290

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41590

American (AMR)

AF:

0.00418

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00682

AC:

464

AN:

68044

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00522

Hom.:

Bravo

AF:

0.00430

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.00769

AC:

ExAC

AF:

0.00389

AC:

468

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00747

EpiControl

AF:

0.00717

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (3)

Baller-Gerold syndrome (1)

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.2

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.019

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.23

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0053

MutationAssessor

Benign

1.1

PhyloP100

-0.31

PrimateAI

Benign

0.28

Sift4G

Benign

0.33

Polyphen

0.40

Vest4

0.66

MVP

0.72

GERP RS

-4.4

PromoterAI

-0.00080

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Varity_R

0.089

gMVP

0.36

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over