NM_001530.4:c.148G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001530.4(HIF1A):c.148G>C(p.Val50Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00308 in 1,613,578 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 14 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1

Conservation

PhyloP100: 5.80

Publications

11 publications found

Variant links:

Genes affected

HIF1A (HGNC:4910): (hypoxia inducible factor 1 subunit alpha) This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2011]

HIF1A links:

HIF1A-AS3 (HGNC:):

HIF1A-AS3 links:

HIF1A-AS3 (HGNC:54284): (HIF1A antisense RNA 3)

HIF1A-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008302808).

BS2

High AC in GnomAd4 at 325 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4 link	c.148G>C	p.Val50Leu	missense_variant	Exon 2 of 15	ENST00000337138.9	NP_001521.1	Q16665-1D0VY79
HIF1A	NM_001243084.2 link	c.220G>C	p.Val74Leu	missense_variant	Exon 2 of 15		NP_001230013.1	Q16665-3
HIF1A	NM_181054.3 link	c.148G>C	p.Val50Leu	missense_variant	Exon 2 of 14		NP_851397.1	Q16665-2
HIF1A-AS3	NR_144368.1 link	n.214-3477C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9 link	c.148G>C	p.Val50Leu	missense_variant	Exon 2 of 15	1	NM_001530.4	ENSP00000338018.4		Q16665-1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

325

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00306

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00196

AC:

491

AN:

250582

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.00755

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00253

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00317

AC:

4639

AN:

1461262

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

2238

AN XY:

726906

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33454

American (AMR)

AF:

0.00103

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00808

AC:

211

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00189

AC:

163

AN:

86164

European-Finnish (FIN)

AF:

0.000450

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00359

AC:

3996

AN:

1111692

Other (OTH)

AF:

0.00316

AC:

191

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

201

403

604

806

1007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00213

AC:

325

AN:

152316

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41570

American (AMR)

AF:

0.00222

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00306

AC:

208

AN:

68030

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00298

Hom.:

Bravo

AF:

0.00216

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00182

AC:

221

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Maffucci syndrome

Pathogenic:1

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;T;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

M;.;M;.

PhyloP100

5.8

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.95

P;D;.;.

Vest4

0.62

MutPred

0.32

.;Gain of disorder (P = 0.1617);.;.;

MVP

0.49

MPC

0.97

ClinPred

0.035

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.47

Mutation Taster

=290/10

polymorphism

(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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NM_001530.4:c.148G>C

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