chr8-31120315-G-A

Position:

chr8-31120315-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000553.6(WRN):c.2521G>A(p.Ala841Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,612,894 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A841P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.12

Variant links:

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4214319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.2521G>A	p.Ala841Thr	missense_variant	21/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
WRN	ENST00000298139.7 linkuse as main transcript	c.2521G>A	p.Ala841Thr	missense_variant	21/35	1	NM_000553.6	P1
WRN	ENST00000521620.5 linkuse as main transcript	n.1154G>A		non_coding_transcript_exon_variant	9/23	1
WRN	ENST00000520169.1 linkuse as main transcript	n.360G>A		non_coding_transcript_exon_variant	1/3	3
WRN	ENST00000650667.1 linkuse as main transcript	c.*2135G>A		3_prime_UTR_variant, NMD_transcript_variant	20/34

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251160

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460990

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726794

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Oct 22, 2021

The c.2521G>A (p.A841T) alteration is located in exon 21 (coding exon 20) of the WRN gene. This alteration results from a G to A substitution at nucleotide position 2521, causing the alanine (A) at amino acid position 841 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Werner syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 841 of the WRN protein (p.Ala841Thr). This variant is present in population databases (rs748169173, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 195567). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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 provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.044

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.33

Sift

Uncertain

0.028

Sift4G

Uncertain

0.042

Polyphen

0.82

Vest4

0.22

MutPred

0.46

Gain of phosphorylation at A841 (P = 0.0657);

MVP

0.81

MPC

0.34

ClinPred

0.29

GERP RS

4.8

Varity_R

0.54

gMVP

0.56

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