NM_004260.4:c.2467G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004260.4(RECQL4):c.2467G>A(p.Glu823Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,555,340 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 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. E823G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2O:1

Conservation

PhyloP100: 0.134

Publications

6 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020927489).

BP6

Variant 8-144513135-C-T is Benign according to our data. Variant chr8-144513135-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135141.

BS2

High Homozygotes in GnomAdExome4 at 2 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.2467G>A	p.Glu823Lys	missense	Exon 15 of 21	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.2467G>A	p.Glu823Lys	missense	Exon 15 of 20	NP_001399948.1
RECQL4	NM_001413036.1		c.2467G>A	p.Glu823Lys	missense	Exon 15 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.2467G>A	p.Glu823Lys	missense	Exon 15 of 21	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.1396G>A	p.Glu466Lys	missense	Exon 14 of 20	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.2374G>A	p.Glu792Lys	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

146134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000215

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000213

AC:

AN:

201436

AF XY:

0.000202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00247

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.000400

GnomAD4 exome

AF:

0.000144

AC:

203

AN:

1409108

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

100

AN XY:

694024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32578

American (AMR)

AF:

0.000218

AC:

AN:

41306

Ashkenazi Jewish (ASJ)

AF:

0.00308

AC:

AN:

23078

East Asian (EAS)

AF:

0.00

AC:

AN:

38852

South Asian (SAS)

AF:

0.000204

AC:

AN:

78382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5510

European-Non Finnish (NFE)

AF:

0.0000840

AC:

AN:

1083722

Other (OTH)

AF:

0.000275

AC:

AN:

58094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000150

AC:

AN:

146232

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

AN XY:

70694

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

39600

American (AMR)

AF:

0.000215

AC:

AN:

13978

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

3446

East Asian (EAS)

AF:

0.000204

AC:

AN:

4914

South Asian (SAS)

AF:

0.00

AC:

AN:

4634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

67200

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.000356

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.000160

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Baller-Gerold syndrome (1)

Hereditary cancer-predisposing syndrome (1)

not specified (2)

RECQL4-related disorder (1)

Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.6

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.018

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.012

MetaRNN

Benign

0.021

MutationAssessor

Benign

0.080

PhyloP100

0.13

PrimateAI

Benign

0.37

Sift4G

Benign

0.80

Polyphen

0.23

Vest4

0.22

MVP

0.74

GERP RS

2.1

PromoterAI

0.0097

Neutral

(source)

Varity_R

0.12

gMVP

0.58

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over