rs869312844

Positions:

• chr6-142761469-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006734.4(HIVEP2):​c.5614dupG​(p.Glu1872fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIVEP2 NM_006734.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57

Genes affected

HIVEP2 (HGNC:4921): (HIVEP zinc finger 2) This gene encodes a member of a family of closely related, large, zinc finger-containing transcription factors. The encoded protein regulates transcription by binding to regulatory regions of various cellular and viral genes that maybe involved in growth, development and metastasis. The protein contains the ZAS domain comprised of two widely separated regions of zinc finger motifs, a stretch of highly acidic amino acids and a serine/threonine-rich sequence. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PP5: Variant 6-142761469-T-TC is Pathogenic according to our data. Variant chr6-142761469-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 224795.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIVEP2	NM_006734.4	c.5614dupG	p.Glu1872fs	frameshift_variant	8/10	ENST00000367603.8	NP_006725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIVEP2	ENST00000367603.8	c.5614dupG	p.Glu1872fs	frameshift_variant	8/10	1	NM_006734.4	ENSP00000356575.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 43 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 20, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2016

The c.5614dupG variant in the HIVEP2 gene has been observed in internal GeneDx whole exome sequencing data in association with developmental delay, hypertonia and spasticity. The c.5614dupG variant causes a frameshift starting with codon Glutamic Acid 1872, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Glu1872GlyfsX16. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5614dupG variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.5614dupG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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: rs869312844; hg19: chr6-143082606;