rs878854138

Variant names:

• chr8-31141751-GTC-TTT
• rs878854138
• NM_000553.6:c.3209_3211delGTCinsTTT

Variant summary

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

The NM_000553.6(WRN):​c.3209_3211delGTCinsTTT​(p.CysPro1070PheSer) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.42

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.3209_3211delGTCinsTTT	p.CysPro1070PheSer	missense_variant		ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3209_3211delGTCinsTTT	p.CysPro1070PheSer	missense_variant		1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.1842_1844delGTCinsTTT		non_coding_transcript_exon_variant	Exon 14 of 23	1
WRN	ENST00000650667.1	n.*2823_*2825delGTCinsTTT		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000498593.1
WRN	ENST00000650667.1	n.*2823_*2825delGTCinsTTT		3_prime_UTR_variant	Exon 25 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Uncertain:2

Aug 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3209_3211delinsTTT, is a complex sequence change that replaces two amino acids, cysteine and proline with phenyalanine and serine at codons 1070-1071 of the WRN protein (p.Cys1070_Pro1071delinsPheSer). The cysteine and proline residues are moderately conserved. This variant is reported as two separate single-nucleotide changes in population databases (c.3209G>T, ExAC 0.1% and c.3211C>T, ExAC 0.1%). However, in the read data for all individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.3209_3211delinsTTT) and indicates that this variant is very likely present in the population databases at 0.1%. This variant has not been reported in the literature in individuals with WRN-related disease. ClinVar contains an entry for this variant (Variation ID: 238148). While algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that the two missense changes, p.Cys1070Phe and p.Pro1071Ser are likely to be tolerated independently, it is uncertain how these two amino acid changes in combination affect protein function. 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. -

May 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854138; hg19: chr8-30999267;