rs2228220

Positions:

• chr6-12123016-A-G
• chr6-12123016-A-T

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.3221A>G​(p.Asn1074Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,994 control chromosomes in the GnomAD database, including 9,228 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 0.11 (1140 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8088 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0240

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=0.001280725).
• BP6: Variant 6-12123016-A-G is Benign according to our data. Variant chr6-12123016-A-G is described in ClinVar as [Benign]. Clinvar id is 402936.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIVEP1	NM_002114.4	c.3221A>G	p.Asn1074Ser	missense_variant	4/9	ENST00000379388.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIVEP1	ENST00000379388.7	c.3221A>G	p.Asn1074Ser	missense_variant	4/9	1	NM_002114.4	P2
HIVEP1	ENST00000541134.5	c.3221A>G	p.Asn1074Ser	missense_variant	4/9	5		A2
HIVEP1	ENST00000627968.2	c.-3083A>G		5_prime_UTR_variant	4/8	5
HIVEP1	ENST00000442081.6	c.166+3082A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17415 AN: 152090 Hom.: 1133 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0957

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.106 AC: 26502 AN: 249158 Hom.: 1623 AF XY: 0.110 AC XY: 14890 AN XY: 135194

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.0664

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.0592

Gnomad NFE exome AF: 0.0980

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.100 AC: 146625 AN: 1461786 Hom.: 8088 Cov.: 39 AF XY: 0.103 AC XY: 74817 AN XY: 727184

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0691

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.0596

Gnomad4 NFE exome AF: 0.0945

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.115 AC: 17452 AN: 152208 Hom.: 1140 Cov.: 32 AF XY: 0.113 AC XY: 8437 AN XY: 74436

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0942

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0544

Gnomad4 NFE AF: 0.0957

Gnomad4 OTH AF: 0.127

Alfa AF: 0.105 Hom.: 2358

Bravo AF: 0.118

TwinsUK AF: 0.0939 AC: 348

ALSPAC AF: 0.0929 AC: 358

ESP6500AA AF: 0.153 AC: 574

ESP6500EA AF: 0.0885 AC: 725

ExAC AF: 0.110 AC: 13237

Asia WGS AF: 0.169 AC: 589 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.104

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: MAF -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.40
DANN	Benign	0.26
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.61	T;.
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.42	T;T
Vest4		0.010
MPC		0.069
ClinPred		0.0018	T
GERP RS		-0.52
gMVP		0.071

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: rs2228220; hg19: chr6-12123249; COSMIC: COSV65100135; COSMIC: COSV65100135;