rs200941778

Positions:

chr8-144515368-C-T

Variant summary

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

The NM_001413043.1(RECQL4):c.-120G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

RECQL4
NM_001413043.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.249

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 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=0.0088098645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.1348G>A	p.Val450Met	missense_variant	7/21	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.1348G>A	p.Val450Met	missense_variant	7/21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 linkuse as main transcript	c.277G>A	p.Val93Met	missense_variant	6/20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000532846.2 linkuse as main transcript	c.232G>A	p.Val78Met	missense_variant	3/9	5		ENSP00000476551.1	V9GYA3
RECQL4	ENST00000688394.1 linkuse as main transcript	n.371G>A		non_coding_transcript_exon_variant	1/4

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000291

AC:

AN:

247666

Hom.:

AF XY:

0.000215

AC XY:

AN XY:

134878

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.000499

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1460374

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

726460

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000828

Gnomad4 ASJ exome

AF:

0.00287

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000571

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00483

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000202

Hom.:

Bravo

AF:

0.000514

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000182

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 03, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter 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

Oct 17, 2022

The RECQL4 c.1348G>A (p.Val450Met) missense change has a maximum non-founder subpopulation frequency of 0.099% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect on protein function, but to our knowledge these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with RECQL4-associated disorders. 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

Mar 13, 2022

- -

RECQL4-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

The RECQL4 c.1348G>A variant is predicted to result in the amino acid substitution p.Val450Met. This variant has been reported in a cohort of individuals presenting with pancreatic ductal adenocarcinoma (Appendix Table 2, Hu et al. 2020. PubMed ID: 32659497) and in a general cohort of patients with a history of cancer (eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant is reported in 0.27% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from uncertain to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/239695/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Baller-Gerold syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Benign

2.1

DANN

Benign

0.47

DEOGEN2

Benign

0.015

T;T

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.0088

T;T

PrimateAI

Benign

0.41

Sift4G

Benign

0.17

T;T

Polyphen

0.57

.;P

Vest4

0.24

MVP

0.51

GERP RS

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.26

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