8-144514359-G-A

Position:

chr8-144514359-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000617875.6(RECQL4):c.1708C>T(p.Arg570Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,600,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R570Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

RECQL4
ENST00000617875.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 1.34

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021208763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.1708C>T	p.Arg570Trp	missense_variant	11/21	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.1708C>T	p.Arg570Trp	missense_variant	11/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.637C>T	p.Arg213Trp	missense_variant	10/20	1		ENSP00000483145
RECQL4	ENST00000534626.6 linkuse as main transcript	c.79C>T	p.Arg27Trp	missense_variant	2/8	5		ENSP00000477457
RECQL4	ENST00000532846.2 linkuse as main transcript	c.565C>T	p.Arg189Trp	missense_variant	7/9	5		ENSP00000476551

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000343

AC:

AN:

239318

Hom.:

AF XY:

0.000352

AC XY:

AN XY:

130556

show subpopulations

Gnomad AFR exome

AF:

0.0000682

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.0000486

Gnomad NFE exome

AF:

0.000307

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.000541

AC:

783

AN:

1447900

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

389

AN XY:

718234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000626

Gnomad4 OTH exome

AF:

0.000686

GnomAD4 genome

AF:

0.000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000394

Hom.:

Bravo

AF:

0.000329

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000274

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Aug 31, 2022

The RECQL4 c.1708C>T (p.Arg570Trp) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about the 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Dec 09, 2021

- -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces arginine with tryptophan at codon 570 of the RECQL4 protein (p.Arg570Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373178405, gnomAD 0.1%). 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: 135130). 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 not expected to disrupt RECQL4 protein function with a negative 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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.15

T;T

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.021

T;T

PrimateAI

Benign

0.22

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

.;D

Vest4

0.41

MVP

0.74

GERP RS

3.3

Varity_R

0.49

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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