8-31085197-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000553.6(WRN):​c.1382C>T​(p.Thr461Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,612,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.490
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010497719).
BP6
Variant 8-31085197-C-T is Benign according to our data. Variant chr8-31085197-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404029.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00027 (41/151724) while in subpopulation SAS AF= 0.0025 (12/4806). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WRNNM_000553.6 linkc.1382C>T p.Thr461Met missense_variant Exon 11 of 35 ENST00000298139.7 NP_000544.2 Q14191

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkc.1382C>T p.Thr461Met missense_variant Exon 11 of 35 1 NM_000553.6 ENSP00000298139.5 Q14191
WRNENST00000651642.1 linkc.596C>T p.Thr199Met missense_variant Exon 4 of 4 ENSP00000498779.1 A0A494C0Y6
WRNENST00000650667.1 linkn.*996C>T non_coding_transcript_exon_variant Exon 10 of 34 ENSP00000498593.1 A0A494C0M3
WRNENST00000650667.1 linkn.*996C>T 3_prime_UTR_variant Exon 10 of 34 ENSP00000498593.1 A0A494C0M3

Frequencies

GnomAD3 genomes
AF:
0.000270
AC:
41
AN:
151608
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000364
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000394
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.00249
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000481
GnomAD3 exomes
AF:
0.000374
AC:
94
AN:
251006
Hom.:
0
AF XY:
0.000449
AC XY:
61
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.000495
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00131
Gnomad SAS exome
AF:
0.00199
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000131
AC:
192
AN:
1460708
Hom.:
1
Cov.:
30
AF XY:
0.000183
AC XY:
133
AN XY:
726728
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000582
Gnomad4 SAS exome
AF:
0.00159
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000270
AC:
41
AN:
151724
Hom.:
0
Cov.:
32
AF XY:
0.000297
AC XY:
22
AN XY:
74156
show subpopulations
Gnomad4 AFR
AF:
0.000362
Gnomad4 AMR
AF:
0.000394
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00250
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000476
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.000193
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000429
AC:
52

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Werner syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 08, 2025- -
Ovarian cancer Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan UniversityJan 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
13
DANN
Benign
0.81
DEOGEN2
Benign
0.051
T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.0055
N
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.0024
T
MetaRNN
Benign
0.010
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.32
N
REVEL
Benign
0.032
Sift
Benign
0.23
T
Sift4G
Benign
0.25
T
Polyphen
0.54
P
Vest4
0.15
MVP
0.38
MPC
0.068
ClinPred
0.0021
T
GERP RS
1.1
Varity_R
0.012
gMVP
0.22

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.

Other links and lift over

dbSNP: rs371602600; hg19: chr8-30942713; COSMIC: COSV53296326; COSMIC: COSV53296326; API