6-12119983-C-T

Variant names:

• chr6-12119983-C-T
• rs1408465101
• NM_002114.4:c.188C>T

Variant summary

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

The NM_002114.4(HIVEP1):​c.188C>T​(p.Pro63Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,742 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

HIVEP1 (HGNC:4920): (HIVEP zinc finger 1) This gene encodes a transcription factor belonging to the ZAS family, members of which are large proteins that contain a ZAS domain - a modular protein structure consisting of a pair of C2H2 zinc fingers with an acidic-rich region and a serine/threonine-rich sequence. These proteins bind specifically to the DNA sequence motif, GGGACTTTCC, found in the enhancer elements of several viral promoters, including human immunodeficiency virus (HIV), and to related sequences found in the enhancer elements of a number of cellular promoters. This protein binds to this sequence motif, suggesting a role in the transcriptional regulation of both viral and cellular genes. [provided by RefSeq, Oct 2011]

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
HIVEP1	NM_002114.4	c.188C>T	p.Pro63Leu	missense_variant	Exon 4 of 9	ENST00000379388.7	NP_002105.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIVEP1	ENST00000379388.7	c.188C>T	p.Pro63Leu	missense_variant	Exon 4 of 9	1	NM_002114.4	ENSP00000368698.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246386 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458742 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.188C>T (p.P63L) alteration is located in exon 4 (coding exon 3) of the HIVEP1 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the proline (P) at amino acid position 63 to be replaced by a leucine (L). 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
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	.;T;.;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;.;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.78	T
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.1	D;D;.;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Benign	0.22	T;T;D;D;T
Vest4		0.77, 0.58
MutPred		0.44		Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);
MVP		0.40
MPC		0.47
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.17

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: rs1408465101; hg19: chr6-12120216;