rs201883228

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A746T) has been classified as Uncertain significance.

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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Baller-Gerold syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
Rothmund-Thomson syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Rothmund-Thomson syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
osteosarcoma
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
rapadilino syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

RECQL4 links:

ENSG00000265393 (HGNC:):

ENSG00000265393 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4 link	c.2237C>T	p.Ala746Val	missense_variant	Exon 14 of 21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6 link	c.2237C>T	p.Ala746Val	missense_variant	Exon 14 of 21	1	NM_004260.4	ENSP00000482313.2		O94761

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

GnomAD2 exomes

AF:

0.000231

AC:

AN:

242430

AF XY:

0.000188

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 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

African (AFR)

AF:

0.000120

AC:

AN:

33470

American (AMR)

AF:

0.000716

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000431

AC:

479

AN:

1111746

Other (OTH)

AF:

0.000149

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000578

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000617

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41588

American (AMR)

AF:

0.00353

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Apr 28, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Aug 13, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 18, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

6.2

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

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over