8-144513057-C-T

Position:

chr8-144513057-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004260.4(RECQL4):c.2545G>A(p.Val849Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000494 in 1,578,360 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V849L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 1.19

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07512605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2545G>A	p.Val849Met	missense_variant	15/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2545G>A	p.Val849Met	missense_variant	15/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1474G>A	p.Val492Met	missense_variant	14/20	1
	ENST00000580385.1 linkuse as main transcript	n.271+220C>T		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.718G>A	p.Val240Met	missense_variant	6/8	5

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000767

AC:

AN:

195490

Hom.:

AF XY:

0.0000658

AC XY:

AN XY:

106320

show subpopulations

Gnomad AFR exome

AF:

0.000641

Gnomad AMR exome

AF:

0.0000698

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000139

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000471

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1426110

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

706240

show subpopulations

Gnomad4 AFR exome

AF:

0.000214

Gnomad4 AMR exome

AF:

0.0000504

Gnomad4 ASJ exome

AF:

0.0000399

Gnomad4 EAS exome

AF:

0.0000528

Gnomad4 SAS exome

AF:

0.000110

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000256

Gnomad4 OTH exome

AF:

0.0000508

GnomAD4 genome

AF:

0.000171

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000840

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 27, 2021

DNA sequence analysis of the RECQL4 gene demonstrated a sequence change, c.2545G>A, in exon 15 results in an amino acid change, p.Val849Met. This sequence change does not appear to have been previously described in individuals with RECQL4-related disorders and has been described in the gnomAD database with a low population frequency of 0.071% in the African subpopulation (dbSNP rs201661055). The p.Val849Met change affects a highly conserved amino acid residue located in a domain of the RECQL4 protein that is not known to be functional. The p.Val849Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val849Met change remains unknown at this time. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 28, 2015

- -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 849 of the RECQL4 protein (p.Val849Met). This variant is present in population databases (rs201661055, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 239737). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RECQL4 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.10

T;T

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.075

T;T

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.43

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.97

.;D

Vest4

0.40

MVP

0.27

GERP RS

1.6

Varity_R

0.037

gMVP

0.59

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

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