8-31068328-G-T

Variant names:

• chr8-31068328-G-T
• rs1339616347
• NM_000553.6:c.724+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000553.6(WRN):​c.724+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000691 in 1,448,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002113615: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Werner syndrome (PMID:20443122). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (Invitae).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WRN NM_000553.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.52
• 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.4, offset of -17, new splice context is: aagGTttgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002113615: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Werner syndrome (PMID: 20443122). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (Invitae).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-31068328-G-T is Pathogenic according to our data. Variant chr8-31068328-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 523380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.724+1G>T		splice_donor 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.724+1G>T		splice_donor intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.724+1G>T		splice_donor intron	N/A	ENSP00000636235.1
	WRN	ENST00000860283.1		c.724+1G>T		splice_donor intron	N/A	ENSP00000530342.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448216 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 720754

African (AFR) AF: 0.00 AC: 0 AN: 33230

American (AMR) AF: 0.00 AC: 0 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 85618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1100952

Other (OTH) AF: 0.00 AC: 0 AN: 59818

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Werner syndrome (2)
1	-	-	Type 2 diabetes mellitus;C0086543:Cataract;C0240538:Convex nasal ridge;C0349588:Short stature;C0424448:Mask-like facies;C5574742:Decreased body weight (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.5
GERP RS		4.9
PromoterAI		-0.0050	Neutral
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1339616347; hg19: chr8-30925844;