rs2228213

Variant names:

• chr6-12124622-G-A
• rs2228213
• NM_002114.4:c.4827G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-12124622-G-A
• chr6-12124622-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002114.4(HIVEP1):​c.4827G>A​(p.Met1609Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,613,710 control chromosomes in the GnomAD database, including 87,650 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1609V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (6157 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81493 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.614
• Publications: 51 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004592508).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIVEP1	NM_002114.4	c.4827G>A	p.Met1609Ile	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.4827G>A	p.Met1609Ile	missense_variant	Exon 4 of 9	1	NM_002114.4	ENSP00000368698.2

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39975 AN: 151990 Hom.: 6165 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.281

GnomAD2 exomes AF: 0.300 AC: 74761 AN: 249464 AF XY: 0.305

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.330 AC: 481654 AN: 1461602 Hom.: 81493 Cov.: 42 AF XY: 0.329 AC XY: 239101 AN XY: 727118

African (AFR) AF: 0.0849 AC: 2841 AN: 33480

American (AMR) AF: 0.245 AC: 10971 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9193 AN: 26136

East Asian (EAS) AF: 0.255 AC: 10135 AN: 39696

South Asian (SAS) AF: 0.265 AC: 22870 AN: 86256

European-Finnish (FIN) AF: 0.344 AC: 18353 AN: 53392

Middle Eastern (MID) AF: 0.254 AC: 1466 AN: 5768

European-Non Finnish (NFE) AF: 0.348 AC: 386937 AN: 1111770

Other (OTH) AF: 0.313 AC: 18888 AN: 60380

GnomAD4 genome AF: 0.263 AC: 39963 AN: 152108 Hom.: 6157 Cov.: 32 AF XY: 0.260 AC XY: 19337 AN XY: 74350

African (AFR) AF: 0.0961 AC: 3990 AN: 41526

American (AMR) AF: 0.279 AC: 4264 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1200 AN: 3468

East Asian (EAS) AF: 0.232 AC: 1196 AN: 5166

South Asian (SAS) AF: 0.265 AC: 1278 AN: 4820

European-Finnish (FIN) AF: 0.333 AC: 3517 AN: 10576

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23522 AN: 67958

Other (OTH) AF: 0.283 AC: 598 AN: 2116

Alfa AF: 0.325 Hom.: 35833

Bravo AF: 0.255

TwinsUK AF: 0.356 AC: 1321

ALSPAC AF: 0.342 AC: 1319

ESP6500AA AF: 0.0912 AC: 375

ESP6500EA AF: 0.343 AC: 2879

ExAC AF: 0.299 AC: 36126

Asia WGS AF: 0.250 AC: 869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.26
DANN	Benign	0.54
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	T;.
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.98	T
PhyloP100		0.61
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.29	.;N
REVEL	Benign	0.048
Sift	Benign	0.16	.;T
Sift4G	Benign	0.37	T;T
Vest4		0.021
MutPred		0.16		Loss of ubiquitination at K1604 (P = 0.0825);Loss of ubiquitination at K1604 (P = 0.0825);
MPC		0.094
ClinPred		0.0059	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.10
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228213; hg19: chr6-12124855; COSMIC: COSV65098859; COSMIC: COSV65098859;