rs140768346

chr8-31141445-G-A

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.2983G>A(p.Ala995Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,614,048 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A995A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (19 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5 O:1
• Conservation: PhyloP100: 0.213

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=0.0060808063).
• BP6: Variant 8-31141445-G-A is Benign according to our data. Variant chr8-31141445-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135428.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=3, Benign=2, Uncertain_significance=2}. Variant chr8-31141445-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00194 (296/152204) while in subpopulation NFE AF= 0.0025 (170/68014). AF 95% confidence interval is 0.00219. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.2983G>A	p.Ala995Thr	missense_variant	25/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.2983G>A	p.Ala995Thr	missense_variant	25/35	1	NM_000553.6	P1
WRN	ENST00000521620.5	n.1616G>A		non_coding_transcript_exon_variant	13/23	1
WRN	ENST00000650667.1	c.*2597G>A		3_prime_UTR_variant, NMD_transcript_variant	24/34

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00239 AC: 601 AN: 251400 Hom.: 8 AF XY: 0.00260 AC XY: 353 AN XY: 135866

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00263 AC: 3842 AN: 1461844 Hom.: 19 Cov.: 30 AF XY: 0.00274 AC XY: 1991 AN XY: 727218

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00406

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74408

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00361 Hom.: 14

Bravo AF: 0.00206

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2019	This variant is associated with the following publications: (PMID: 28051113, 24728327) -
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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	WRN: BP4, BS2 -

Werner syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2016	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.80	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.066
Sift	Benign	0.32	T
Sift4G	Benign	0.30	T
Polyphen		0.017	B
Vest4		0.20
MVP		0.30
MPC		0.24
ClinPred		0.037	T
GERP RS		-2.4
Varity_R		0.11
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs140768346; hg19: chr8-30998961; COSMIC: COSV104591538;