rs78488552

chr8-31154721-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000553.6(WRN):c.3785C>G(p.Thr1262Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00493 in 1,613,518 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (31 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 4.78

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061229944).
• BP6: Variant 8-31154721-C-G is Benign according to our data. Variant chr8-31154721-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135436.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, not_provided=1, Benign=3}. Variant chr8-31154721-C-G is described in Lovd as [Likely_benign]. Variant chr8-31154721-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00273 (416/152242) while in subpopulation NFE AF= 0.00482 (328/67996). AF 95% confidence interval is 0.00439. There are 3 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.3785C>G	p.Thr1262Arg	missense_variant	32/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.3785C>G	p.Thr1262Arg	missense_variant	32/35	1	NM_000553.6	P1
WRN	ENST00000521620.5	n.2418C>G		non_coding_transcript_exon_variant	20/23	1
WRN	ENST00000650667.1	c.*3399C>G		3_prime_UTR_variant, NMD_transcript_variant	31/34

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152124 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00482

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00273 AC: 686 AN: 251350 Hom.: 6 AF XY: 0.00286 AC XY: 389 AN XY: 135862

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00525

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00515 AC: 7531 AN: 1461276 Hom.: 31 Cov.: 30 AF XY: 0.00490 AC XY: 3564 AN XY: 726966

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000581

Gnomad4 NFE exome AF: 0.00644

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152242 Hom.: 3 Cov.: 33 AF XY: 0.00227 AC XY: 169 AN XY: 74458

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00482

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00481 Hom.: 1

Bravo AF: 0.00304

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00274 AC: 332

Asia WGS AF: 0.000289 AC: 1 AN: 3470

EpiCase AF: 0.00474

EpiControl AF: 0.00504

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2022	Variant summary: WRN c.3785C>G (p.Thr1262Arg) results in a non-conservative amino acid change located in the Helicase Helix-turn-helix domain (IPR029491) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 251350 control chromosomes, predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.3785C>G in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Werner syndrome Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	WRN: BP1, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	This variant is associated with the following publications: (PMID: 23891399, 26546047, 27153395, 24728327) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.061	T
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.88
MPC		0.42
ClinPred		0.045	T
GERP RS		5.5
Varity_R		0.68
gMVP		0.88

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: rs78488552; hg19: chr8-31012237; COSMIC: COSV99988182;