6-142753138-T-G

Position:

• chr6-142753138-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006734.4(HIVEP2):​c.7310A>C​(p.Asp2437Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HIVEP2 NM_006734.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.24

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HIVEP2. . Gene score misZ 1.8295 (greater than the threshold 3.09). Trascript score misZ 3.809 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 43.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09483725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIVEP2	NM_006734.4	c.7310A>C	p.Asp2437Ala	missense_variant	10/10	ENST00000367603.8	NP_006725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIVEP2	ENST00000367603.8	c.7310A>C	p.Asp2437Ala	missense_variant	10/10	1	NM_006734.4	ENSP00000356575	P1
	ENST00000437067.1	n.96-368T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 43 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 19, 2020

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM6,BP1. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 2437 of the HIVEP2 protein (p.Asp2437Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HIVEP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 931829). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.017
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	.;.;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.90	N;N;N
REVEL	Benign	0.078
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.020	B;B;B
Vest4		0.18
MutPred		0.15		Loss of solvent accessibility (P = 0.0249);Loss of solvent accessibility (P = 0.0249);Loss of solvent accessibility (P = 0.0249);
MVP		0.068
MPC		0.23
ClinPred		0.28	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.058

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: rs1774961744; hg19: chr6-143074275;