rs369158322

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The ENST00000298139.7(WRN):ā€‹c.3686A>Cā€‹(p.Gln1229Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1229L) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)

Consequence

WRN
ENST00000298139.7 missense, splice_region

Scores

3
16
Splicing: ADA: 0.9257
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.55
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-31150454-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 5450.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WRNNM_000553.6 linkuse as main transcriptc.3686A>C p.Gln1229Pro missense_variant, splice_region_variant 31/35 ENST00000298139.7 NP_000544.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkuse as main transcriptc.3686A>C p.Gln1229Pro missense_variant, splice_region_variant 31/351 NM_000553.6 ENSP00000298139 P1
WRNENST00000521620.5 linkuse as main transcriptn.2319A>C splice_region_variant, non_coding_transcript_exon_variant 19/231
WRNENST00000650667.1 linkuse as main transcriptc.*3300A>C splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant 30/34 ENSP00000498593

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000723
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251402
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000723
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 14, 2022In 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. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). 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: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 846289). This variant has not been reported in the literature in individuals affected with WRN-related conditions. This variant is present in population databases (rs369158322, gnomAD 0.007%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1229 of the WRN protein (p.Gln1229Pro). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.28
T
Eigen
Benign
0.0096
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.015
T
MetaRNN
Uncertain
0.72
D
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.9
D
REVEL
Benign
0.18
Sift
Benign
0.057
T
Sift4G
Benign
0.14
T
Polyphen
0.0020
B
Vest4
0.85
MVP
0.61
MPC
0.092
ClinPred
0.32
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.66
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.93
dbscSNV1_RF
Pathogenic
0.73
SpliceAI score (max)
0.39
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.39
Position offset: 1

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: rs369158322; hg19: chr8-31007970; API