rs201883228

Positions:

Variant summary

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

The NM_004260.4(RECQL4):c.2237C>T(p.Ala746Val) variant causes a missense change. The variant allele was found at a frequency of 0.000382 in 1,609,684 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A746A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.18

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:

RECQL4 (HGNC:):

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	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2237C>T	p.Ala746Val	missense_variant	14/21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2237C>T	p.Ala746Val	missense_variant	14/21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1166C>T	p.Ala389Val	missense_variant	13/20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 linkuse as main transcript	c.605C>T	p.Ala202Val	missense_variant	5/8	5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 linkuse as main transcript	n.272-162G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000578

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

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:

0.000353

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000231

AC:

AN:

242430

Hom.:

AF XY:

0.000188

AC XY:

AN XY:

132946

show subpopulations

Gnomad AFR exome

AF:

0.000202

Gnomad AMR exome

AF:

0.000814

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000200

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000362

AC:

527

AN:

1457314

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

248

AN XY:

725128

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000431

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000578

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.000239

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000117

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2021

The c.2237C>T (p.A746V) alteration is located in exon 14 (coding exon 14) of the RECQL4 gene. This alteration results from a C to T substitution at nucleotide position 2237, causing the alanine (A) at amino acid position 746 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2021

Reported in an individual with sagittal synostosis, but further clinical information, information on the zygosity or presence of a second RECQL4 variant, and familial segregation information were not included (Sewda et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31555317, 30651579) -

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

Apr 18, 2023

The RECQL4 c.2237C>T (p.Ala746Val) missense change has a maximum subpopulation frequency of 0.082% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about a benign or pathogenic effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant was reported in an individual with nonsyndromic saggital craniosynostosis, however the zygosity or identification of a second variant was not indicated (PMID: 30651579). 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. -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 746 of the RECQL4 protein (p.Ala746Val). This variant is present in population databases (rs201883228, gnomAD 0.08%). This missense change has been observed in individual(s) with sagittal craniosynostosis (PMID: 30651579). ClinVar contains an entry for this variant (Variation ID: 239719). 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. -

RECQL4-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The RECQL4 c.2237C>T variant is predicted to result in the amino acid substitution p.Ala746Val. This variant was reported in an individual with nonsyndromic sagittal craniosynostosis; however, the zygosity or presence of a second variant was not specified (Sewda et al. 2019. PubMed ID: 30651579). This variant is reported in 0.082% of alleles in individuals of Latino descent in gnomAD and in ClinVar this variant has been interpreted as uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/239719/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Benign

0.72

DEOGEN2

Benign

0.37

T;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.52

D;D

PrimateAI

Uncertain

0.71

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.88

MVP

0.55

GERP RS

5.7

Varity_R

0.80

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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