8-31096768-A-T

Variant names:

• chr8-31096768-A-T
• rs878854134
• NM_000553.6:c.1899A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000553.6(WRN):​c.1899A>T​(p.Leu633Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 1,453,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L633I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: WRN NM_000553.6 missense, splice_region
• Scores: Splicing: ADA: 0.0005062
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• osteosarcoma

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24303871).

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.1899A>T	p.Leu633Phe	missense splice_region	Exon 17 of 35	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.1899A>T	p.Leu633Phe	missense splice_region	Exon 17 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.532A>T		splice_region non_coding_transcript_exon	Exon 5 of 23
	WRN	ENST00000966176.1		c.1899A>T	p.Leu633Phe	missense splice_region	Exon 17 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000815 AC: 2 AN: 245502 AF XY: 0.00000754

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000757 AC: 11 AN: 1453726 Hom.: 0 Cov.: 33 AF XY: 0.00000553 AC XY: 4 AN XY: 723038

African (AFR) AF: 0.0000301 AC: 1 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 84692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000812 AC: 9 AN: 1108972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60114

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Werner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.57	N
PhyloP100		1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	0.051	T
Sift4G	Uncertain	0.050	T
Polyphen		0.99	D
Vest4		0.15
MutPred		0.65		Gain of methylation at K632 (P = 0.0316)
MVP		0.42
MPC		0.37
ClinPred		0.15	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.36
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.084
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: rs878854134; hg19: chr8-30954284;