1-41510704-C-T

Position:

• chr1-41510704-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024503.5(HIVEP3):​c.6968G>A​(p.Arg2323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00749 in 1,526,540 control chromosomes in the GnomAD database, including 164 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (154 hom.)
• Consequence: HIVEP3 NM_024503.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.00400

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020682514).
• BP6: Variant 1-41510704-C-T is Benign according to our data. Variant chr1-41510704-C-T is described in ClinVar as [Benign]. Clinvar id is 3042394.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00561 (854/152276) while in subpopulation SAS AF= 0.0464 (224/4826). AF 95% confidence interval is 0.0414. There are 10 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIVEP3	NM_024503.5	c.6968G>A	p.Arg2323Gln	missense_variant	9/9	ENST00000372583.6	NP_078779.2
HIVEP3	NM_001127714.3	c.6965G>A	p.Arg2322Gln	missense_variant	8/8		NP_001121186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIVEP3	ENST00000372583.6	c.6968G>A	p.Arg2323Gln	missense_variant	9/9	1	NM_024503.5	ENSP00000361664	P5
HIVEP3	ENST00000372584.5	c.6965G>A	p.Arg2322Gln	missense_variant	8/8	1		ENSP00000361665	A2
HIVEP3	ENST00000643665.1	c.6965G>A	p.Arg2322Gln	missense_variant	8/8			ENSP00000494598	A2
HIVEP3	ENST00000460604.1	n.1895G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 855 AN: 152158 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.0100 AC: 1395 AN: 138950 Hom.: 23 AF XY: 0.0126 AC XY: 947 AN XY: 75366

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00831

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0440

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00770 AC: 10587 AN: 1374264 Hom.: 154 Cov.: 34 AF XY: 0.00885 AC XY: 5973 AN XY: 674976

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00825

Gnomad4 EAS exome AF: 0.0000823

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.00205

Gnomad4 NFE exome AF: 0.00589

Gnomad4 OTH exome AF: 0.00769

GnomAD4 genome AF: 0.00561 AC: 854 AN: 152276 Hom.: 10 Cov.: 33 AF XY: 0.00639 AC XY: 476 AN XY: 74464

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0464

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00612 Hom.: 3

Bravo AF: 0.00454

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000765 AC: 3

ESP6500EA AF: 0.00453 AC: 35

ExAC AF: 0.00749 AC: 856

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HIVEP3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 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	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.60	.;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.64	.;N;N
REVEL	Benign	0.034
Sift	Benign	0.42	.;T;T
Sift4G	Benign	0.54	.;T;T
Polyphen		0.0030	B;B;B
Vest4		0.080, 0.063
MPC		0.21
ClinPred		0.0065	T
GERP RS		0.15
Varity_R		0.028
gMVP		0.037

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: rs200138511; hg19: chr1-41976375; COSMIC: COSV56017830;