rs761231404

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004260.4(RECQL4):c.2704C>T(p.Arg902Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,590,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R902Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 0.441

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2704C>T	p.Arg902Trp	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.2704C>T	p.Arg902Trp	missense_variant	15/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1633C>T	p.Arg545Trp	missense_variant	14/20	1
	ENST00000580385.1 linkuse as main transcript	n.271+61G>A		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.877C>T	p.Arg293Trp	missense_variant	6/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000181

AC:

AN:

1438486

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

713580

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.0000241

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000259

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.0000396

Gnomad4 NFE exome

AF:

0.0000164

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

RECQL4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2023

The RECQL4 c.2704C>T variant is predicted to result in the amino acid substitution p.Arg902Trp. This variant was reported in an individual with sporadic breast cancer (Table 2, Moradian et al. 2021. PubMed ID: 33558524). This variant is reported in 0.0011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-145738281-G-A) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/459424). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 902 of the RECQL4 protein (p.Arg902Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 459424). 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

0.15

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

Cadd

Uncertain

Dann

Benign

0.76

DEOGEN2

Benign

0.067

T;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.70

D;D

PrimateAI

Uncertain

0.49

Sift4G

Uncertain

0.023

D;D

Polyphen

1.0

.;D

Vest4

0.65

MVP

0.76

GERP RS

2.9

Varity_R

0.24

gMVP

0.56

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