8-31096778-C-T

Position:

• chr8-31096778-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_000553.6(WRN):​c.1909C>T​(p.Arg637Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,609,108 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 1.43

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000372 (543/1459272) while in subpopulation MID AF= 0.00399 (23/5764). AF 95% confidence interval is 0.00273. There are 1 homozygotes in gnomad4_exome. There are 271 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.1909C>T	p.Arg637Trp	missense_variant	17/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1909C>T	p.Arg637Trp	missense_variant	17/35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.542C>T		non_coding_transcript_exon_variant	5/23	1
WRN	ENST00000650667.1	n.*1523C>T		non_coding_transcript_exon_variant	16/34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*1523C>T		3_prime_UTR_variant	16/34			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.000321 AC: 48 AN: 149736 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000400

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000576

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000412 AC: 103 AN: 249788 Hom.: 0 AF XY: 0.000392 AC XY: 53 AN XY: 135134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000372 AC: 543 AN: 1459272 Hom.: 1 Cov.: 33 AF XY: 0.000373 AC XY: 271 AN XY: 726072

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000579

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000327 AC: 49 AN: 149836 Hom.: 0 Cov.: 31 AF XY: 0.000316 AC XY: 23 AN XY: 72888

Gnomad4 AFR AF: 0.0000490

Gnomad4 AMR AF: 0.000399

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000576

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000666 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000362 AC: 44

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The WRN p.Arg637Trp variant was identified in 1 of 18 Werner syndrome patients; the variant was identified as a compound heterozygous mutation in a male with Werner syndrome, osteoporosis and cancer (Uhrhammer_2006_PMID:16786514). The variant was identified in dbSNP (ID: rs148286708) and ClinVar (classified as uncertain significance by EGL Genetic Diagnotics and Invitae) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 111 of 279850 chromosomes (0 homozygous) at a frequency of 0.0003966 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 7 of 10332 chromosomes (freq: 0.000678), European (non-Finnish) in 79 of 128100 chromosomes (freq: 0.000617), Other in 4 of 7152 chromosomes (freq: 0.000559), Latino in 17 of 35294 chromosomes (freq: 0.000482), South Asian in 3 of 30544 chromosomes (freq: 0.000098) and European (Finnish) in 1 of 23934 chromosomes (freq: 0.000042), but was not observed in the African or East Asian populations. The p.Arg637 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Werner syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2021	DNA sequence analysis of the WRN gene demonstrated a sequence change, c.1909C>T, in exon 17 that results in an amino acid change, p.Arg637Trp. This sequence change has been described in gnomAD with a frequency of 0.062% in Non-Finnish European sub-population (dbSNP rs148286708). The p.Arg637Trp change affects a highly conserved amino acid residue located in a domain of the WRN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg637Trp substitution. This particular sequence change has been reported in the compound heterozygous state in one individual with Werner syndrome, osteoporosis, and cancer (PMID: 16786514). Due to the lack of sufficient evidences, the clinical significance of the p.Arg637Trp change remains unknown at this time. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

WRN-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

The WRN c.1909C>T variant is predicted to result in the amino acid substitution p.Arg637Trp. This variant was reported in the compound heterozygous state in an individual with Werner syndrome; however no functional or family segregation studies have confirmed its pathogenicity (Patient 943-1, Uhrhammer et al. 2006. PubMed ID: 16786514). This variant was also reported in an individual with head and neck cancer (Table S3, Cury et al. 2021. PubMed ID: 34598035) and an individual with osteosarcoma (eTable 5, Mirabello et al. 2020. PubMed ID: 32191290). This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/135421). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.65
MPC		0.40
ClinPred		0.21	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs148286708; hg19: chr8-30954294;