Genetic Variant WRN:p.Arg877Ser (chr8-31124522-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000553.6(WRN):c.2631G>C(p.Arg877Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,556 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R877T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense, splice_region

Scores

Splicing: ADA: 0.9056

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.766

Publications

0 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

WRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	Exon 22 of 35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 link	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	Exon 22 of 35	1	NM_000553.6	ENSP00000298139.5		Q14191

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458556

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725778

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109416

Other (OTH)

AF:

0.0000166

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

0.018

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

0.77

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.18

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0090

Polyphen

0.94

Vest4

0.52

MutPred

0.51

Loss of MoRF binding (P = 0.0305);

MVP

0.47

MPC

0.096

ClinPred

0.75

GERP RS

4.7

Varity_R

0.60

gMVP

0.72

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.40

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over