rs2228213

chr6-12124622-G-Achr6-12124622-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002114.4(HIVEP1):c.4827G>A(p.Met1609Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,710 control chromosomes in the GnomAD database, including 87,650 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.26 (6157 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81493 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.614

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004592508).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP1	NM_002114.4	c.4827G>A	p.Met1609Ile	missense_variant	4/9	ENST00000379388.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP1	ENST00000379388.7	c.4827G>A	p.Met1609Ile	missense_variant	4/9	1	NM_002114.4	P2
HIVEP1	ENST00000541134.5	c.4827G>A	p.Met1609Ile	missense_variant	4/9	5		A2
HIVEP1	ENST00000627968.2	c.-1477G>A		5_prime_UTR_variant	4/8	5
HIVEP1	ENST00000442081.6	c.166+4688G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39975 AN: 151990 Hom.: 6165 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.281

GnomAD3 exomes AF: 0.300 AC: 74761 AN: 249464 Hom.: 12109 AF XY: 0.305 AC XY: 41329 AN XY: 135348

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.232

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.330 AC: 481654 AN: 1461602 Hom.: 81493 Cov.: 42 AF XY: 0.329 AC XY: 239101 AN XY: 727118

Gnomad4 AFR exome AF: 0.0849

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.352

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.263 AC: 39963 AN: 152108 Hom.: 6157 Cov.: 32 AF XY: 0.260 AC XY: 19337 AN XY: 74350

Gnomad4 AFR AF: 0.0961

Gnomad4 AMR AF: 0.279

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.283

Alfa AF: 0.331 Hom.: 20114

Bravo AF: 0.255

TwinsUK AF: 0.356 AC: 1321

ALSPAC AF: 0.342 AC: 1319

ESP6500AA AF: 0.0912 AC: 375

ESP6500EA AF: 0.343 AC: 2879

ExAC AF: 0.299 AC: 36126

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.26
Dann	Benign	0.54
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	T;.
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.19	T
Sift4G	Benign	0.37	T;T
Vest4		0.021
MutPred		0.16		Loss of ubiquitination at K1604 (P = 0.0825);Loss of ubiquitination at K1604 (P = 0.0825);
MPC		0.094
ClinPred		0.0059	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.10

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: rs2228213; hg19: chr6-12124855; COSMIC: COSV65098859; COSMIC: COSV65098859;