rs368611522

Positions:

chr8-144513135-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000617875.6(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
ENST00000617875.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.134

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 135141.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=2, not_provided=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2467G>A	p.Glu823Lys	missense_variant	15/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2467G>A	p.Glu823Lys	missense_variant	15/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1396G>A	p.Glu466Lys	missense_variant	14/20	1		ENSP00000483145
	ENST00000580385.1 linkuse as main transcript	n.271+298C>T		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.640G>A	p.Glu214Lys	missense_variant	6/8	5		ENSP00000477457

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

GnomAD3 exomes

AF:

0.000213

AC:

AN:

201436

Hom.:

AF XY:

0.000202

AC XY:

AN XY:

108886

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 SAS exome

AF:

0.000272

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000218

Gnomad4 ASJ exome

AF:

0.00308

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000204

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000840

Gnomad4 OTH exome

AF:

0.000275

GnomAD4 genome

AF:

0.000150

AC:

AN:

146232

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

AN XY:

70694

show subpopulations

Gnomad4 AFR

AF:

0.000101

Gnomad4 AMR

AF:

0.000215

Gnomad4 ASJ

AF:

0.00203

Gnomad4 EAS

AF:

0.000204

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 09, 2021	DNA sequence analysis of the RECQL4 gene demonstrated a sequence change, c.2467G>A, in exon 15 that results in an amino acid change, p.Glu823Lys. This sequence change has been described in the gnomAD database with a frequency of 0.25% in the Ashkenazi Jewish subpopulation (dbSNP rs368611522). The p.Glu823Lys change affects a moderately conserved amino acid residue located in a domain of the RECQL4 protein that is not known to be functional. The p.Glu823Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). This sequence change does not appear to have been previously described in individuals with RECQL4-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu823Lys change remains unknown at this time. -

Rothmund-Thomson syndrome type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

May 17, 2024

The RECQL4 c.2467G>A (p.Glu823Lys) missense change has a maximum subpopulation frequency of 0.032% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with RECQL4-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

RECQL4-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2024

The RECQL4 c.2467G>A variant is predicted to result in the amino acid substitution p.Glu823Lys. This variant was identified in a healthy individual in a study of cancer susceptibility genes (Table S1. Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote. This variant is listed in ClinVar with conflicting interpretations of uncertain, likely benign, and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/135141/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 23, 2021

- -

Baller-Gerold syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.6

DANN

Benign

0.75

DEOGEN2

Benign

0.018

T;T

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.021

T;T

MutationAssessor

Benign

0.080

.;N

PrimateAI

Benign

0.37

Sift4G

Benign

0.80

T;T

Polyphen

0.23

.;B

Vest4

0.22

MVP

0.74

GERP RS

2.1

Varity_R

0.12

gMVP

0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over