rs377494266

Variant summary

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

The NM_004260.4(RECQL4):c.1109G>A(p.Arg370His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,609,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R370C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.45

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 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.1109G>A	p.Arg370His	missense_variant	5/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.1109G>A	p.Arg370His	missense_variant	5/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.38G>A	p.Arg13His	missense_variant	4/20	1
RECQL4	ENST00000524998.1 linkuse as main transcript	c.632G>A	p.Arg211His	missense_variant	3/4	3
RECQL4	ENST00000532846.2 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152230

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000365

AC:

AN:

246896

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134506

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1457546

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

724428

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74368

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RECQL4-related condition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The RECQL4 c.1109G>A variant is predicted to result in the amino acid substitution p.Arg370His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. 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

Oct 14, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 370 of the RECQL4 protein (p.Arg370His). This variant is present in population databases (rs377494266, gnomAD 0.02%). 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: 407034). 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. 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

0.12

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.10

Cadd

Uncertain

Dann

Benign

0.83

DEOGEN2

Benign

0.11

T;T

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0098

MetaRNN

Uncertain

0.47

T;T

PrimateAI

Benign

0.45

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

.;D

Vest4

0.64

MVP

0.70

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.28

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