8-31058158-A-C

Variant names:

• chr8-31058158-A-C
• rs11574175
• NM_000553.6:c.-76-214A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000553.6(WRN):​c.-76-214A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 152,254 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.060 (284 hom., cov: 33)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.324
• Publications: 1 publications found

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]

WRN Gene-Disease associations (from GenCC):

• Werner syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-31058158-A-C is Benign according to our data. Variant chr8-31058158-A-C is described in ClinVar as [Benign]. Clinvar id is 1250354.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.076 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.-76-214A>C		intron_variant	Intron 1 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.-76-214A>C		intron_variant	Intron 1 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000650667.1	n.-76-214A>C		intron_variant	Intron 1 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9083 AN: 152134 Hom.: 283 Cov.: 33

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.0741

Gnomad SAS AF: 0.0822

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0598

Gnomad OTH AF: 0.0603

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0597 AC: 9089 AN: 152254 Hom.: 284 Cov.: 33 AF XY: 0.0602 AC XY: 4479 AN XY: 74448

African (AFR) AF: 0.0613 AC: 2548 AN: 41554

American (AMR) AF: 0.0388 AC: 594 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3470

East Asian (EAS) AF: 0.0743 AC: 385 AN: 5184

South Asian (SAS) AF: 0.0827 AC: 399 AN: 4824

European-Finnish (FIN) AF: 0.0696 AC: 737 AN: 10590

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0598 AC: 4069 AN: 68014

Other (OTH) AF: 0.0597 AC: 126 AN: 2110

Alfa AF: 0.0614 Hom.: 35

Bravo AF: 0.0567

Asia WGS AF: 0.0800 AC: 278 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.72
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11574175; hg19: chr8-30915674;