NM_000553.6:c.673C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000553.6(WRN):​c.673C>T​(p.Arg225*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R225R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

WRN
NM_000553.6 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.963

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • Werner syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
  • osteosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-31068276-C-T is Pathogenic according to our data. Variant chr8-31068276-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 404010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WRNNM_000553.6 linkc.673C>T p.Arg225* stop_gained Exon 7 of 35 ENST00000298139.7 NP_000544.2 Q14191

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkc.673C>T p.Arg225* stop_gained Exon 7 of 35 1 NM_000553.6 ENSP00000298139.5 Q14191
WRNENST00000650667.1 linkn.*287C>T non_coding_transcript_exon_variant Exon 6 of 34 ENSP00000498593.1 A0A494C0M3
WRNENST00000650667.1 linkn.*287C>T 3_prime_UTR_variant Exon 6 of 34 ENSP00000498593.1 A0A494C0M3
WRNENST00000651642.1 linkc.-33C>T upstream_gene_variant ENSP00000498779.1 A0A494C0Y6

Frequencies

GnomAD3 genomes
AF:
0.00000661
AC:
1
AN:
151210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000815
AC:
2
AN:
245266
AF XY:
0.0000151
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000412
AC:
6
AN:
1454564
Hom.:
0
Cov.:
30
AF XY:
0.00000553
AC XY:
4
AN XY:
723542
show subpopulations
African (AFR)
AF:
0.0000300
AC:
1
AN:
33358
American (AMR)
AF:
0.00
AC:
0
AN:
44436
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25900
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39540
South Asian (SAS)
AF:
0.0000117
AC:
1
AN:
85658
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52958
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5726
European-Non Finnish (NFE)
AF:
0.00000361
AC:
4
AN:
1107024
Other (OTH)
AF:
0.00
AC:
0
AN:
59964
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000661
AC:
1
AN:
151210
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73778
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41044
American (AMR)
AF:
0.00
AC:
0
AN:
15170
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10348
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67880
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000495
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Werner syndrome Pathogenic:3
May 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg225*) in the WRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 404010). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Jul 03, 2023
Baylor Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 07, 2021
Institute of Human Genetics, University of Leipzig Medical Center
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Criteria applied: PVS1,PM3,PM2_SUP -

WRN-related disorder Pathogenic:1
Jul 13, 2023
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The WRN c.673C>T variant is predicted to result in premature protein termination (p.Arg225*). This variant has been reported in the heterozygous state in individuals from an breast cancer exome sequencing cohort and an exome carrier screening cohort (Table S5, Maxwell et al. 2016. PubMed ID: 27153395; Table S1, Capalbo et al. 2019. PubMed ID: 31589614). This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-30925792-C-T). Nonsense variants in WRN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.22
Eigen_PC
Benign
-0.052
FATHMM_MKL
Benign
0.47
N
PhyloP100
0.96
Vest4
0.72
GERP RS
3.0
PromoterAI
-0.016
Neutral
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.28
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.28
Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs370324188; hg19: chr8-30925792; API