rs151001436

Variant summary

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

The NM_000553.6(WRN):​c.1628A>C​(p.Tyr543Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

1
8
10

Clinical Significance

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

Conservation

PhyloP100: 3.90
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]

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 rank MANE Protein UniProt
WRNNM_000553.6 linkc.1628A>C p.Tyr543Ser missense_variant Exon 13 of 35 ENST00000298139.7 NP_000544.2 Q14191

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkc.1628A>C p.Tyr543Ser missense_variant Exon 13 of 35 1 NM_000553.6 ENSP00000298139.5 Q14191
WRNENST00000521620.5 linkn.329A>C non_coding_transcript_exon_variant Exon 2 of 23 1
WRNENST00000650667.1 linkn.*1242A>C non_coding_transcript_exon_variant Exon 12 of 34 ENSP00000498593.1 A0A494C0M3
WRNENST00000650667.1 linkn.*1242A>C 3_prime_UTR_variant Exon 12 of 34 ENSP00000498593.1 A0A494C0M3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152094
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249076
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134578
show subpopulations
Gnomad AFR exome
AF:
0.000124
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:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459230
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725836
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152094
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74282
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Werner syndrome Uncertain:1
Sep 12, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 458388). This variant has not been reported in the literature in individuals affected with WRN-related conditions. This variant is present in population databases (rs151001436, gnomAD 0.007%). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 543 of the WRN protein (p.Tyr543Ser). -

not provided Uncertain:1
Mar 03, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.040
D
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
2.0
M
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Benign
0.25
Sift
Benign
0.036
D
Sift4G
Uncertain
0.055
T
Polyphen
1.0
D
Vest4
0.54
MVP
0.72
MPC
0.46
ClinPred
0.91
D
GERP RS
4.3
Varity_R
0.82
gMVP
0.87

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.

Other links and lift over

dbSNP: rs151001436; hg19: chr8-30946457; API