rs2228210

Variant names:

• chr6-12121941-A-G
• rs2228210
• NM_002114.4:c.2146A>G

Variant summary

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

The NM_002114.4(HIVEP1):​c.2146A>G​(p.Thr716Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,613,794 control chromosomes in the GnomAD database, including 90,091 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. T716M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (6163 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83928 hom.)
• Consequence: HIVEP1 NM_002114.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• Publications: 29 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=0.003978461).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002114.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIVEP1	NM_002114.4	MANE Select	c.2146A>G	p.Thr716Ala	missense	Exon 4 of 9	NP_002105.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIVEP1	ENST00000379388.7	TSL:1 MANE Select	c.2146A>G	p.Thr716Ala	missense	Exon 4 of 9	ENSP00000368698.2
	HIVEP1	ENST00000478545.2	TSL:4	c.2146A>G	p.Thr716Ala	missense	Exon 4 of 9	ENSP00000418021.2
	HIVEP1	ENST00000487103.6	TSL:2	c.2146A>G	p.Thr716Ala	missense	Exon 4 of 9	ENSP00000417348.2

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39066 AN: 151946 Hom.: 6171 Cov.: 32

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.301 AC: 74911 AN: 248896 AF XY: 0.307

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.334 AC: 488143 AN: 1461730 Hom.: 83928 Cov.: 47 AF XY: 0.333 AC XY: 242491 AN XY: 727160

African (AFR) AF: 0.0560 AC: 1873 AN: 33476

American (AMR) AF: 0.245 AC: 10953 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9218 AN: 26136

East Asian (EAS) AF: 0.256 AC: 10173 AN: 39698

South Asian (SAS) AF: 0.272 AC: 23446 AN: 86256

European-Finnish (FIN) AF: 0.344 AC: 18389 AN: 53394

Middle Eastern (MID) AF: 0.256 AC: 1474 AN: 5768

European-Non Finnish (NFE) AF: 0.354 AC: 393607 AN: 1111898

Other (OTH) AF: 0.315 AC: 19010 AN: 60390

GnomAD4 genome AF: 0.257 AC: 39045 AN: 152064 Hom.: 6163 Cov.: 32 AF XY: 0.254 AC XY: 18878 AN XY: 74298

African (AFR) AF: 0.0677 AC: 2810 AN: 41524

American (AMR) AF: 0.277 AC: 4227 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1201 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1203 AN: 5166

South Asian (SAS) AF: 0.272 AC: 1309 AN: 4820

European-Finnish (FIN) AF: 0.333 AC: 3511 AN: 10542

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23799 AN: 67948

Other (OTH) AF: 0.278 AC: 586 AN: 2108

Alfa AF: 0.322 Hom.: 33114

Bravo AF: 0.248

TwinsUK AF: 0.361 AC: 1340

ALSPAC AF: 0.347 AC: 1336

ESP6500AA AF: 0.0657 AC: 274

ESP6500EA AF: 0.350 AC: 2940

ExAC AF: 0.299 AC: 36244

Asia WGS AF: 0.253 AC: 877 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.060
DANN	Benign	0.31
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.055
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.027
Sift	Benign	0.36	T
Sift4G	Benign	0.50	T
Vest4		0.015
MPC		0.084
ClinPred		0.013	T
GERP RS		-7.6
gMVP		0.17
Mutation Taster		=98/2	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: rs2228210; hg19: chr6-12122174; COSMIC: COSV65101743; COSMIC: COSV65101743;