chr8-31100837-CT-C

Variant names:

• chr8-31100837-CT-C
• rs397723919
• NM_000553.6:c.1982-5delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.1982-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73564 hom., cov: 0)
  • Exomes 𝑓: 1.0 (727296 hom.)
• Consequence: WRN NM_000553.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.219
• Publications: 6 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-31100837-CT-C is Benign according to our data. Variant chr8-31100837-CT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.1982-5delT		splice_region intron	N/A	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.1982-11delT		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.615-11delT		intron	N/A
	WRN	ENST00000966176.1		c.1982-11delT		intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.983 AC: 149400 AN: 151948 Hom.: 73507 Cov.: 0

Gnomad AFR AF: 0.941

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.988

GnomAD2 exomes AF: 0.996 AC: 249718 AN: 250824 AF XY: 0.997

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1456935 AN: 1459454 Hom.: 727296 Cov.: 0 AF XY: 0.999 AC XY: 725122 AN XY: 726194

African (AFR) AF: 0.936 AC: 31296 AN: 33436

American (AMR) AF: 0.997 AC: 44584 AN: 44704

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26102 AN: 26102

East Asian (EAS) AF: 1.00 AC: 39668 AN: 39668

South Asian (SAS) AF: 1.00 AC: 86095 AN: 86106

European-Finnish (FIN) AF: 1.00 AC: 53249 AN: 53250

Middle Eastern (MID) AF: 0.998 AC: 5747 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1110058 AN: 1110120

Other (OTH) AF: 0.997 AC: 60136 AN: 60310

GnomAD4 genome AF: 0.983 AC: 149516 AN: 152066 Hom.: 73564 Cov.: 0 AF XY: 0.984 AC XY: 73107 AN XY: 74326

African (AFR) AF: 0.941 AC: 38993 AN: 41446

American (AMR) AF: 0.996 AC: 15212 AN: 15278

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5154 AN: 5154

South Asian (SAS) AF: 1.00 AC: 4820 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10578 AN: 10578

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68002 AN: 68006

Other (OTH) AF: 0.988 AC: 2084 AN: 2110

Alfa AF: 0.994 Hom.: 13619

Bravo AF: 0.981

Asia WGS AF: 0.998 AC: 3471 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Werner syndrome (3)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397723919; hg19: chr8-30958353; COSMIC: COSV53296284;