rs1800391

Positions:

• chr8-31081188-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.1161G>A​(p.Met387Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,613,922 control chromosomes in the GnomAD database, including 5,480 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (425 hom., cov: 32)
  • Exomes 𝑓: 0.078 (5055 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.111

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015295148).
• BP6: Variant 8-31081188-G-A is Benign according to our data. Variant chr8-31081188-G-A is described in ClinVar as [Benign]. Clinvar id is 130757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31081188-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.1161G>A	p.Met387Ile	missense_variant	9/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1161G>A	p.Met387Ile	missense_variant	9/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000651642.1	c.456G>A	p.Met152Ile	missense_variant	3/4			ENSP00000498779
WRN	ENST00000650667.1	c.*775G>A		3_prime_UTR_variant, NMD_transcript_variant	8/34			ENSP00000498593

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9462 AN: 152120 Hom.: 424 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0741

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0660

GnomAD3 exomes AF: 0.0752 AC: 18831 AN: 250442 Hom.: 891 AF XY: 0.0800 AC XY: 10827 AN XY: 135374

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0607

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.0821

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0778 AC: 113722 AN: 1461684 Hom.: 5055 Cov.: 32 AF XY: 0.0802 AC XY: 58332 AN XY: 727136

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0619

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.000857

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0814

Gnomad4 NFE exome AF: 0.0782

Gnomad4 OTH exome AF: 0.0758

GnomAD4 genome AF: 0.0621 AC: 9460 AN: 152238 Hom.: 425 Cov.: 32 AF XY: 0.0642 AC XY: 4780 AN XY: 74430

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0740

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0855

Gnomad4 NFE AF: 0.0817

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0785 Hom.: 1132

Bravo AF: 0.0558

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0716 AC: 276

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.0792 AC: 681

ExAC AF: 0.0751 AC: 9114

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:4

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Wiskott-Aldrich syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.1
DANN	Benign	0.53
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.076
Sift	Benign	0.34	T
Sift4G	Benign	0.26	T
Polyphen		0.20	B
Vest4		0.022
MutPred		0.24		Loss of disorder (P = 0.0513);
MPC		0.078
ClinPred		0.000023	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.091

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: rs1800391; hg19: chr8-30938704; COSMIC: COSV53296756;