14-61732425-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001530.4(HIF1A):c.781G>A(p.Glu261Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,596,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

Publications

1 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:

ENSG00000258667 (HGNC:):

ENSG00000258667 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 -1 ACMG points.

BS2

High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001530.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIF1A	NM_001530.4	MANE Select	c.781G>A	p.Glu261Lys	missense	Exon 7 of 15	NP_001521.1	D0VY79
HIF1A	NM_001243084.2		c.853G>A	p.Glu285Lys	missense	Exon 7 of 15	NP_001230013.1	Q16665-3
HIF1A	NM_181054.3		c.781G>A	p.Glu261Lys	missense	Exon 7 of 14	NP_851397.1	Q16665-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.781G>A	p.Glu261Lys	missense	Exon 7 of 15	ENSP00000338018.4	Q16665-1
HIF1A	ENST00000539097.2	TSL:1	c.853G>A	p.Glu285Lys	missense	Exon 7 of 15	ENSP00000437955.1	Q16665-3
HIF1A	ENST00000394997.5	TSL:1	c.784G>A	p.Glu262Lys	missense	Exon 7 of 15	ENSP00000378446.1	A8MYV6

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249434

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1444330

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719524

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33098

American (AMR)

AF:

0.0000901

AC:

AN:

44402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00000547

AC:

AN:

1097544

Other (OTH)

AF:

0.0000502

AC:

AN:

59728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000658

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41398

American (AMR)

AF:

0.000523

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

PhyloP100

9.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.43

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.65

MutPred

0.66

Gain of methylation at E262 (P = 0.0128)

MVP

0.63

MPC

1.8

ClinPred

0.96

GERP RS

5.5

Varity_R

0.65

gMVP

0.57

Mutation Taster

=22/78

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over