Variant 10-86467470-G-GTATA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_015045.5(WAPL):c.2178_2179insTATA(p.Leu727TyrfsTer4) variant causes a frameshift 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

WAPL
NM_015045.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.251

Variant links:

Genes affected

WAPL (HGNC:23293): (WAPL cohesin release factor) Involved in several processes, including negative regulation of DNA replication; negative regulation of chromatin binding activity; and regulation of sister chromatid cohesion. Located in several cellular components, including Golgi apparatus; intercellular bridge; and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

WAPL links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WAPL	NM_015045.5 linkuse as main transcript	c.2178_2179insTATA	p.Leu727TyrfsTer4	frameshift_variant	9/19	ENST00000298767.10
WAPL	NM_001318328.2 linkuse as main transcript	c.2160_2161insTATA	p.Leu721TyrfsTer4	frameshift_variant	9/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WAPL	ENST00000298767.10 linkuse as main transcript	c.2178_2179insTATA	p.Leu727TyrfsTer4	frameshift_variant	9/19	1	NM_015045.5	P1	Q7Z5K2-1
WAPL	ENST00000372075.2 linkuse as main transcript	c.36_37insTATA	p.Leu13TyrfsTer4	frameshift_variant	1/10	2
WAPL	ENST00000489996.1 linkuse as main transcript	n.228_229insTATA		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.2175_2178dupTATA (p.L727Yfs*4) alteration, located in exon 9 (coding exon 8) of the WAPL gene, consists of a duplication of TATA at position 2175, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of WAPL has not been established as a mechanism of disease. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over