rs1002222882

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000553.6(WRN):​c.919A>T​(p.Thr307Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 0.401
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.040784925).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WRNNM_000553.6 linkc.919A>T p.Thr307Ser missense_variant 9/35 ENST00000298139.7 NP_000544.2 Q14191

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WRNENST00000298139.7 linkc.919A>T p.Thr307Ser missense_variant 9/351 NM_000553.6 ENSP00000298139.5 Q14191
WRNENST00000651642.1 linkc.214A>T p.Thr72Ser missense_variant 3/4 ENSP00000498779.1 A0A494C0Y6
WRNENST00000650667.1 linkn.*533A>T non_coding_transcript_exon_variant 8/34 ENSP00000498593.1 A0A494C0M3
WRNENST00000650667 linkn.*533A>T 3_prime_UTR_variant 8/33 ENSP00000498593.1 A0A494C0M3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152160
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:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461594
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727088
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Bravo
AF:
0.00000756
Asia WGS
AF:
0.000289
AC:
1
AN:
3476

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 19, 2024The c.919A>T (p.T307S) alteration is located in exon 9 (coding exon 8) of the WRN gene. This alteration results from a A to T substitution at nucleotide position 919, causing the threonine (T) at amino acid position 307 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 05, 2024This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 307 of the WRN protein (p.Thr307Ser). This variant is not present in population databases (gnomAD no frequency). 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: 458504). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine 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. -
not provided Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Uncertain significance and reported on 11-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
0.31
DANN
Benign
0.48
DEOGEN2
Benign
0.060
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.035
N
LIST_S2
Benign
0.37
T
M_CAP
Benign
0.0038
T
MetaRNN
Benign
0.041
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.28
N
REVEL
Benign
0.018
Sift
Benign
0.41
T
Sift4G
Benign
0.55
T
Polyphen
0.017
B
Vest4
0.032
MutPred
0.14
Gain of disorder (P = 0.0454);
MVP
0.27
MPC
0.060
ClinPred
0.031
T
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.016
gMVP
0.15

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1002222882; hg19: chr8-30938462; API