rs34477820

chr8-31058542-A-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.95A>G(p.Lys32Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00386 in 1,613,424 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K32E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: WRN NM_000553.6 missense, splice_region
• Scores: Splicing: ADA: 0.9915
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 5.79

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=0.0048146844).
• BP6: Variant 8-31058542-A-G is Benign according to our data. Variant chr8-31058542-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135423.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=3, Uncertain_significance=1}. Variant chr8-31058542-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.003 (457/152366) while in subpopulation NFE AF= 0.00541 (368/68036). AF 95% confidence interval is 0.00495. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.95A>G	p.Lys32Arg	missense_variant, splice_region_variant	2/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.95A>G	p.Lys32Arg	missense_variant, splice_region_variant	2/35	1	NM_000553.6	P1
WRN	ENST00000650667.1	c.95A>G	p.Lys32Arg	missense_variant, splice_region_variant, NMD_transcript_variant	2/34

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00305 AC: 764 AN: 250438 Hom.: 7 AF XY: 0.00307 AC XY: 416 AN XY: 135362

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.000787

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00395 AC: 5766 AN: 1461058 Hom.: 19 Cov.: 30 AF XY: 0.00396 AC XY: 2877 AN XY: 726816

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000859

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00478

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74514

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00450 Hom.: 3

Bravo AF: 0.00286

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00358 AC: 435

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	WRN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	This variant is associated with the following publications: (PMID: 28063943) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 05, 2020	- -

Werner syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.020	D
Polyphen		0.70	P
Vest4		0.21
MVP		0.75
MPC		0.28
ClinPred		0.031	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.060		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: rs34477820; hg19: chr8-30916058; COSMIC: COSV99035806;