8-31087874-A-T

Position:

• chr8-31087874-A-T

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.1530A>T​(p.Glu510Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,612,848 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. E510E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2 O:1
• Conservation: PhyloP100: -0.131

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=0.0029921234).
• BP6: Variant 8-31087874-A-T is Benign according to our data. Variant chr8-31087874-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135416.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=1, Uncertain_significance=2, Benign=1}. Variant chr8-31087874-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00046 (70/152322) while in subpopulation EAS AF= 0.00925 (48/5188). AF 95% confidence interval is 0.00717. There are 2 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.1530A>T	p.Glu510Asp	missense_variant	12/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.1530A>T	p.Glu510Asp	missense_variant	12/35	1	NM_000553.6	P1
WRN	ENST00000521620.5	n.231A>T		non_coding_transcript_exon_variant	1/23	1
WRN	ENST00000650667.1	c.*1144A>T		3_prime_UTR_variant, NMD_transcript_variant	11/34

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000742 AC: 186 AN: 250820 Hom.: 3 AF XY: 0.000730 AC XY: 99 AN XY: 135576

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00811

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000374 AC: 546 AN: 1460526 Hom.: 1 Cov.: 31 AF XY: 0.000363 AC XY: 264 AN XY: 726594

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00631

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74492

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00925

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000667 AC: 81

Asia WGS AF: 0.00549 AC: 19 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Werner syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.13
DANN	Benign	0.14
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.51	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.049
Sift	Benign	1.0	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.23		Loss of methylation at K506 (P = 0.1751);
MVP		0.21
MPC		0.059
ClinPred		0.0085	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.069
gMVP		0.23

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: rs149565907; hg19: chr8-30945390; COSMIC: COSV53296091;