rs2228212

Positions:

• chr6-12124354-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002114.4(HIVEP1):​c.4559C>G​(p.Ala1520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,613,108 control chromosomes in the GnomAD database, including 96,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (7692 hom., cov: 32)
  • Exomes 𝑓: 0.35 (88931 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.702

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028498769).
• BP6: Variant 6-12124354-C-G is Benign according to our data. Variant chr6-12124354-C-G is described in ClinVar as [Benign]. Clinvar id is 402937.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP1	NM_002114.4	c.4559C>G	p.Ala1520Gly	missense_variant	4/9	ENST00000379388.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP1	ENST00000379388.7	c.4559C>G	p.Ala1520Gly	missense_variant	4/9	1	NM_002114.4	P2
HIVEP1	ENST00000541134.5	c.4559C>G	p.Ala1520Gly	missense_variant	4/9	5		A2
HIVEP1	ENST00000627968.2	c.-1745C>G		5_prime_UTR_variant	4/8	5
HIVEP1	ENST00000442081.6	c.166+4420C>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47254 AN: 151910 Hom.: 7693 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.324 AC: 80788 AN: 249220 Hom.: 13752 AF XY: 0.323 AC XY: 43675 AN XY: 135226

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.269

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.346 AC: 504949 AN: 1461080 Hom.: 88931 Cov.: 44 AF XY: 0.344 AC XY: 250034 AN XY: 726930

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.354

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.311 AC: 47264 AN: 152028 Hom.: 7692 Cov.: 32 AF XY: 0.313 AC XY: 23263 AN XY: 74314

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.319

Alfa AF: 0.349 Hom.: 3224

Bravo AF: 0.301

TwinsUK AF: 0.353 AC: 1308

ALSPAC AF: 0.350 AC: 1348

ESP6500AA AF: 0.209 AC: 815

ESP6500EA AF: 0.355 AC: 2947

ExAC AF: 0.320 AC: 38622

Asia WGS AF: 0.207 AC: 719 AN: 3478

EpiCase AF: 0.357

EpiControl AF: 0.363

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.18
DANN	Benign	0.36
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	T;.
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.16	T
Sift4G	Benign	0.37	T;T
Vest4		0.055
MPC		0.091
ClinPred		0.0013	T
GERP RS		-3.8
gMVP		0.013

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: rs2228212; hg19: chr6-12124587; COSMIC: COSV65098809; COSMIC: COSV65098809;