chr8-31080874-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000553.6(WRN):​c.847A>G​(p.Ile283Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,604,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. I283L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -1.70

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: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03204447).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WRNNM_000553.6 linkc.847A>G p.Ile283Val missense_variant Exon 9 of 35 ENST00000298139.7 NP_000544.2 Q14191

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkc.847A>G p.Ile283Val missense_variant Exon 9 of 35 1 NM_000553.6 ENSP00000298139.5 Q14191
WRNENST00000651642.1 linkc.142A>G p.Ile48Val missense_variant Exon 3 of 4 ENSP00000498779.1 A0A494C0Y6
WRNENST00000650667.1 linkn.*461A>G non_coding_transcript_exon_variant Exon 8 of 34 ENSP00000498593.1 A0A494C0M3
WRNENST00000650667.1 linkn.*461A>G 3_prime_UTR_variant Exon 8 of 34 ENSP00000498593.1 A0A494C0M3

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152092
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000249
AC:
6
AN:
240922
AF XY:
0.0000459
show subpopulations
Gnomad AFR exome
AF:
0.0000659
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:
0.0000455
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000399
AC:
58
AN:
1452114
Hom.:
0
Cov.:
31
AF XY:
0.0000388
AC XY:
28
AN XY:
722094
show subpopulations
African (AFR)
AF:
0.0000610
AC:
2
AN:
32800
American (AMR)
AF:
0.00
AC:
0
AN:
43008
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25764
East Asian (EAS)
AF:
0.0000253
AC:
1
AN:
39584
South Asian (SAS)
AF:
0.0000119
AC:
1
AN:
83806
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53218
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5168
European-Non Finnish (NFE)
AF:
0.0000469
AC:
52
AN:
1108842
Other (OTH)
AF:
0.0000334
AC:
2
AN:
59924
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
3
6
10
13
16
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:
0.0000526
AC:
8
AN:
152092
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74300
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41412
American (AMR)
AF:
0.0000655
AC:
1
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10594
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.456
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

Genome 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
Alfa
AF:
0.0000452
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.000231
AC:
1
ESP6500EA
AF:
0.000117
AC:
1
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Apr 01, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.847A>G (p.I283V) alteration is located in exon 9 (coding exon 8) of the WRN gene. This alteration results from a A to G substitution at nucleotide position 847, causing the isoleucine (I) at amino acid position 283 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Werner syndrome Uncertain:1
Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 283 of the WRN protein (p.Ile283Val). This variant is present in population databases (rs201643901, gnomAD 0.007%). 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: 528182). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.038
DANN
Benign
0.22
DEOGEN2
Benign
0.046
T
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.46
T
M_CAP
Benign
0.0014
T
MetaRNN
Benign
0.032
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.23
N
PhyloP100
-1.7
PrimateAI
Benign
0.24
T
PROVEAN
Benign
0.060
N
REVEL
Benign
0.048
Sift
Benign
0.59
T
Sift4G
Benign
0.29
T
Polyphen
0.0
B
Vest4
0.022
MVP
0.19
MPC
0.056
ClinPred
0.019
T
GERP RS
-12
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.018
gMVP
0.086
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs201643901; hg19: chr8-30938390; API