chr6-12125539-A-G

Variant names:

• chr6-12125539-A-G
• rs1126472
• NM_002114.4:c.5744A>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.5744A>G​(p.Gln1915Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,972 control chromosomes in the GnomAD database, including 11,695 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1769 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9926 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.18

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=0.005001366).
• BP6: Variant 6-12125539-A-G is Benign according to our data. Variant chr6-12125539-A-G is described in ClinVar as [Benign]. Clinvar id is 402938.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIVEP1	NM_002114.4	c.5744A>G	p.Gln1915Arg	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.5744A>G	p.Gln1915Arg	missense_variant	Exon 4 of 9	1	NM_002114.4	ENSP00000368698.2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21238 AN: 152156 Hom.: 1759 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.0550

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.120 AC: 29823 AN: 249166 Hom.: 2052 AF XY: 0.122 AC XY: 16517 AN XY: 135210

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.0882

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.111 AC: 162252 AN: 1461698 Hom.: 9926 Cov.: 34 AF XY: 0.113 AC XY: 82376 AN XY: 727170

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.0915

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.0605

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.140 AC: 21283 AN: 152274 Hom.: 1769 Cov.: 32 AF XY: 0.138 AC XY: 10247 AN XY: 74458

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.0550

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.162

Alfa AF: 0.118 Hom.: 2382

Bravo AF: 0.147

TwinsUK AF: 0.103 AC: 381

ALSPAC AF: 0.104 AC: 401

ESP6500AA AF: 0.205 AC: 789

ESP6500EA AF: 0.100 AC: 823

ExAC AF: 0.123 AC: 14885

Asia WGS AF: 0.175 AC: 608 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: MAF -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0050
DANN	Benign	0.15
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.14	T;.
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.11	.;N
REVEL	Benign	0.015
Sift	Benign	0.56	.;T
Sift4G	Benign	0.54	T;T
Vest4		0.0020
MPC		0.092
ClinPred		0.00030	T
GERP RS		-6.6
gMVP		0.15

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: rs1126472; hg19: chr6-12125772; COSMIC: COSV65101833; COSMIC: COSV65101833;