1-41510858-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024503.5(HIVEP3):c.6814G>A(p.Gly2272Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,613,218 control chromosomes in the GnomAD database, including 3,544 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.088 (1038 hom., cov: 33)
  • Exomes 𝑓: 0.047 (2506 hom.)
• Consequence: HIVEP3 NM_024503.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00200

Genes affected

HIVEP3 (HGNC:13561): (HIVEP zinc finger 3) This gene encodes a member of the human immunodeficiency virus type 1 enhancer-binding protein family. Members of this protein family contain multiple zinc finger and acid-rich (ZAS) domains and serine-threonine rich regions. This protein acts as a transcription factor and is able to regulate nuclear factor kappaB-mediated transcription by binding the kappaB motif in target genes. This protein also binds the recombination signal sequence that flanks the V, D, and J regions of immunoglobulin and T-cell receptors. Alternate splicing results in both coding and non-coding transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.978712E-4).
• BP6: Variant 1-41510858-C-T is Benign according to our data. Variant chr1-41510858-C-T is described in ClinVar as [Benign]. Clinvar id is 402942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP3	NM_024503.5	c.6814G>A	p.Gly2272Arg	missense_variant	9/9	ENST00000372583.6
HIVEP3	NM_001127714.3	c.6811G>A	p.Gly2271Arg	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP3	ENST00000372583.6	c.6814G>A	p.Gly2272Arg	missense_variant	9/9	1	NM_024503.5	P5
HIVEP3	ENST00000372584.5	c.6811G>A	p.Gly2271Arg	missense_variant	8/8	1		A2
HIVEP3	ENST00000643665.1	c.6811G>A	p.Gly2271Arg	missense_variant	8/8			A2
HIVEP3	ENST00000460604.1	n.1741G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13382 AN: 152112 Hom.: 1029 Cov.: 33

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0398

Gnomad OTH AF: 0.0808

GnomAD3 exomes AF: 0.0572 AC: 14287 AN: 249762 Hom.: 684 AF XY: 0.0574 AC XY: 7776 AN XY: 135548

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0343

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.0190

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0467 AC: 68190 AN: 1460988 Hom.: 2506 Cov.: 34 AF XY: 0.0478 AC XY: 34765 AN XY: 726800

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0641

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.0988

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0588

GnomAD4 genome AF: 0.0882 AC: 13427 AN: 152230 Hom.: 1038 Cov.: 33 AF XY: 0.0873 AC XY: 6498 AN XY: 74430

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0590

Gnomad4 EAS AF: 0.0174

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0419

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.0837

Alfa AF: 0.0458 Hom.: 537

Bravo AF: 0.0927

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0426 AC: 164

ESP6500AA AF: 0.206 AC: 909

ESP6500EA AF: 0.0430 AC: 370

ExAC AF: 0.0619 AC: 7508

Asia WGS AF: 0.0940 AC: 327 AN: 3478

EpiCase AF: 0.0391

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 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: MAF -

HIVEP3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	12
Dann	Benign	0.17
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.0065	N
MetaRNN	Benign	0.0010	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.54	T
Polyphen		0.0	B;B;B
Vest4		0.063, 0.058
MutPred		0.044		.;Gain of MoRF binding (P = 0.0891);.;
MPC		0.22
ClinPred		0.0037	T
GERP RS		2.6
Varity_R		0.040
gMVP		0.026

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: rs11809423; hg19: chr1-41976529; COSMIC: COSV56023198;