chr8-31173034-T-C

Position:

• chr8-31173034-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000553.6(WRN):​c.4231T>C​(p.Phe1411Leu) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.862

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25975668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.4231T>C	p.Phe1411Leu	missense_variant	35/35	ENST00000298139.7	NP_000544.2
WRN	XM_011544639.4	c.4150T>C	p.Phe1384Leu	missense_variant	34/34		XP_011542941.1
WRN	XM_011544640.2	c.2632T>C	p.Phe878Leu	missense_variant	23/23		XP_011542942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.4231T>C	p.Phe1411Leu	missense_variant	35/35	1	NM_000553.6	ENSP00000298139	P1
	ENST00000521252.1	n.181+3658A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Werner syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant has not been reported in the literature in individuals with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 458480). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 1411 of the WRN protein (p.Phe1411Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.90	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.057
Sift	Benign	0.069	T
Sift4G	Benign	0.10	T
Polyphen		0.87	P
Vest4		0.19
MutPred		0.15		Loss of methylation at K1413 (P = 0.1105);
MVP		0.67
MPC		0.081
ClinPred		0.57	D
GERP RS		2.8
Varity_R		0.17
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554539890; hg19: chr8-31030550;