1-41510546-G-A

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.7126C>T(p.Pro2376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0559 in 1,576,608 control chromosomes in the GnomAD database, including 3,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (913 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2743 hom.)
• Consequence: HIVEP3 NM_024503.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17

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=0.0012972653).
• BP6: Variant 1-41510546-G-A is Benign according to our data. Variant chr1-41510546-G-A is described in ClinVar as [Benign]. Clinvar id is 402940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP3	NM_024503.5	c.7126C>T	p.Pro2376Ser	missense_variant	9/9	ENST00000372583.6
HIVEP3	NM_001127714.3	c.7123C>T	p.Pro2375Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP3	ENST00000372583.6	c.7126C>T	p.Pro2376Ser	missense_variant	9/9	1	NM_024503.5	P5
HIVEP3	ENST00000372584.5	c.7123C>T	p.Pro2375Ser	missense_variant	8/8	1		A2
HIVEP3	ENST00000643665.1	c.7123C>T	p.Pro2375Ser	missense_variant	8/8			A2
HIVEP3	ENST00000460604.1	n.2053C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0859 AC: 13063 AN: 152078 Hom.: 907 Cov.: 33

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0766

GnomAD3 exomes AF: 0.0659 AC: 12199 AN: 185134 Hom.: 604 AF XY: 0.0671 AC XY: 6630 AN XY: 98832

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.0659

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.00310

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0489

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0527 AC: 75009 AN: 1424412 Hom.: 2743 Cov.: 30 AF XY: 0.0539 AC XY: 38023 AN XY: 704980

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.0641

Gnomad4 ASJ exome AF: 0.0559

Gnomad4 EAS exome AF: 0.00365

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0450

Gnomad4 OTH exome AF: 0.0612

GnomAD4 genome AF: 0.0861 AC: 13100 AN: 152196 Hom.: 913 Cov.: 33 AF XY: 0.0851 AC XY: 6332 AN XY: 74420

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0582

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0369

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0777

Alfa AF: 0.0516 Hom.: 177

Bravo AF: 0.0916

TwinsUK AF: 0.0361 AC: 134

ALSPAC AF: 0.0480 AC: 185

ESP6500AA AF: 0.180 AC: 790

ESP6500EA AF: 0.0496 AC: 426

ExAC AF: 0.0574 AC: 6830

Asia WGS AF: 0.0870 AC: 304 AN: 3478

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

Nov 16, 2019

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	0.16
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Benign	0.044
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.66	N;N;N;N
PrimateAI	Uncertain	0.57	T
Polyphen		0.87	P;P;P
Vest4		0.073, 0.13
MPC		0.30
ClinPred		0.012	T
GERP RS		4.3
Varity_R		0.092
gMVP		0.085

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: rs72669005; hg19: chr1-41976217;