8-31058111-G-A

Variant names:

• chr8-31058111-G-A
• rs7016874
• NM_000553.6:c.-76-261G>A

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.-76-261G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,082 control chromosomes in the GnomAD database, including 7,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (7152 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.358
• Publications: 5 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=-0.85).
• BP6: Variant 8-31058111-G-A is Benign according to our data. Variant chr8-31058111-G-A is described in ClinVar as [Benign]. Clinvar id is 1286012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.-76-261G>A		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.-76-261G>A		intron_variant	Intron 1 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000650667.1	n.-76-261G>A		intron_variant	Intron 1 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42189 AN: 151964 Hom.: 7148 Cov.: 32

Gnomad AFR AF: 0.0747

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.298

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

GnomAD4 genome AF: 0.277 AC: 42188 AN: 152082 Hom.: 7152 Cov.: 32 AF XY: 0.275 AC XY: 20467 AN XY: 74330

African (AFR) AF: 0.0745 AC: 3094 AN: 41540

American (AMR) AF: 0.354 AC: 5403 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1421 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1436 AN: 5176

South Asian (SAS) AF: 0.205 AC: 986 AN: 4816

European-Finnish (FIN) AF: 0.307 AC: 3238 AN: 10546

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25595 AN: 67940

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.316 Hom.: 2245

Bravo AF: 0.277

Asia WGS AF: 0.233 AC: 806 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 28, 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	-0.85
CADD	Benign	5.3
DANN	Benign	0.47
PhyloP100		0.36
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: rs7016874; hg19: chr8-30915627;