8-31150454-A-T

Position:

• chr8-31150454-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000298139.7(WRN):​c.3686A>T​(p.Gln1229Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1229P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN ENST00000298139.7 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.55

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-31150454-A-T is Pathogenic according to our data. Variant chr8-31150454-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 5450.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.3686A>T	p.Gln1229Leu	missense_variant, splice_region_variant	31/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3686A>T	p.Gln1229Leu	missense_variant, splice_region_variant	31/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000521620.5	n.2319A>T		splice_region_variant, non_coding_transcript_exon_variant	19/23	1
WRN	ENST00000650667.1	c.*3300A>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	30/34			ENSP00000498593

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Werner syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.085
Sift	Benign	0.062	T
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.50
MutPred		0.42		Loss of catalytic residue at Q1229 (P = 0.0255);
MVP		0.62
MPC		0.067
ClinPred		0.97	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.58		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs369158322; hg19: chr8-31007970;