Genetic Variant NM_002114.4:c.4559C>G (chr6-12124354-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002114.4(HIVEP1):c.4559C>G(p.Ala1520Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,613,108 control chromosomes in the GnomAD database, including 96,623 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.31 ( 7692 hom., cov: 32)

Exomes 𝑓: 0.35 ( 88931 hom. )

Consequence

HIVEP1
NM_002114.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.702

Publications

22 publications found

Variant links:

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]

HIVEP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028498769).

BP6

Variant 6-12124354-C-G is Benign according to our data. Variant chr6-12124354-C-G is described in ClinVar as Benign. ClinVar VariationId is 402937.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIVEP1	NM_002114.4 link	c.4559C>G	p.Ala1520Gly	missense_variant	Exon 4 of 9	ENST00000379388.7	NP_002105.3	P15822-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIVEP1	ENST00000379388.7 link	c.4559C>G	p.Ala1520Gly	missense_variant	Exon 4 of 9	1	NM_002114.4	ENSP00000368698.2		P15822-1

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47254

AN:

151910

Hom.:

7693

Cov.:

show subpopulations

Gnomad AFR

AF:

0.225

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.371

Gnomad MID

AF:

0.452

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.320

GnomAD2 exomes

AF:

0.324

AC:

80788

AN:

249220

AF XY:

0.323

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.357

Gnomad ASJ exome

AF:

0.360

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.363

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.332

GnomAD4 exome

AF:

0.346

AC:

504949

AN:

1461080

Hom.:

88931

Cov.:

AF XY:

0.344

AC XY:

250034

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.221

AC:

7412

AN:

33472

American (AMR)

AF:

0.354

AC:

15816

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

9324

AN:

26132

East Asian (EAS)

AF:

0.197

AC:

7809

AN:

39700

South Asian (SAS)

AF:

0.272

AC:

23456

AN:

86246

European-Finnish (FIN)

AF:

0.365

AC:

19485

AN:

53338

Middle Eastern (MID)

AF:

0.375

AC:

2165

AN:

5768

European-Non Finnish (NFE)

AF:

0.360

AC:

399585

AN:

1111358

Other (OTH)

AF:

0.330

AC:

19897

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

18105

36210

54315

72420

90525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12602

25204

37806

50408

63010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.311

AC:

47264

AN:

152028

Hom.:

7692

Cov.:

AF XY:

0.313

AC XY:

23263

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.225

AC:

9316

AN:

41476

American (AMR)

AF:

0.330

AC:

5029

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1264

AN:

3470

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5180

South Asian (SAS)

AF:

0.260

AC:

1253

AN:

4810

European-Finnish (FIN)

AF:

0.371

AC:

3916

AN:

10556

Middle Eastern (MID)

AF:

0.462

AC:

135

AN:

292

European-Non Finnish (NFE)

AF:

0.361

AC:

24519

AN:

67956

Other (OTH)

AF:

0.319

AC:

674

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1632

3264

4896

6528

8160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.349

Hom.:

3224

Bravo

AF:

0.301

TwinsUK

AF:

0.353

AC:

1308

ALSPAC

AF:

0.350

AC:

1348

ESP6500AA

AF:

0.209

AC:

815

ESP6500EA

AF:

0.355

AC:

2947

ExAC

AF:

0.320

AC:

38622

Asia WGS

AF:

0.207

AC:

719

AN:

3478

EpiCase

AF:

0.357

EpiControl

AF:

0.363

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.18

(source)

DANN

Benign

0.36

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.52

T;.

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.94

PhyloP100

-0.70

PrimateAI

Benign

0.16

PROVEAN

Benign

-0.98

.;N

REVEL

Benign

0.0020

Sift

Benign

0.47

.;T

Sift4G

Benign

0.37

T;T

Vest4

0.055

MPC

0.091

ClinPred

0.0013

GERP RS

-3.8

gMVP

0.013

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over