rs11549465

Variant names:

Variant summary

Our verdict is The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_001530.4(HIF1A):c.1744C>T (p.Pro582Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene HIF1A is a tumor suppressor gene (CancerMine: 16 TSG, 13 oncogene, 5 driver citations). The gene HIF1A is a known oncogene (CancerMine: 16 TSG, 13 oncogene, 5 driver citations). The gene HIF1A is a cancer driver gene (CancerMine: 16 TSG, 13 oncogene, 5 driver citations). The variant allele was found at a cumulative frequency of 0.0954 (AC=154,031) in the gnomAD database across 1,613,808 control chromosomes, including 7,963 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.188. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). The variant has been observed in cBioPortal in 4 samples across 3 studies and 3 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.078 ( 547 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7416 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:2

Conservation

PhyloP100: 2.79

Publications

409 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

new If you want to explore the variant's impact on the transcript NM_001530.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript

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

GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.188 — exceeds 1% threshold (B1 applied)

Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HIF1A	NM_001530.4	MANE Select	c.1744C>T	p.Pro582Ser	missense	Exon 12 of 15	NP_001521.1	D0VY79
HIF1A	NM_001243084.2		c.1816C>T	p.Pro606Ser	missense	Exon 12 of 15	NP_001230013.1	Q16665-3
HIF1A	NM_181054.3		c.1744C>T	p.Pro582Ser	missense	Exon 12 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.1744C>T	p.Pro582Ser	missense	Exon 12 of 15	ENSP00000338018.4	Q16665-1
HIF1A	ENST00000539097.2	TSL:1	c.1816C>T	p.Pro606Ser	missense	Exon 12 of 15	ENSP00000437955.1	Q16665-3
HIF1A	ENST00000394997.5	TSL:1	c.1747C>T	p.Pro583Ser	missense	Exon 12 of 15	ENSP00000378446.1	A8MYV6

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11893

AN:

152074

Hom.:

548

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0845

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.0482

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0358

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.0985

GnomAD2 exomes

AF:

0.0881

AC:

22150

AN:

251470

AF XY:

0.0928

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.0629

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.0428

Gnomad FIN exome

AF:

0.0389

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.0973

AC:

142148

AN:

1461616

Hom.:

7416

Cov.:

AF XY:

0.0983

AC XY:

71461

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0355

AC:

1187

AN:

33478

American (AMR)

AF:

0.0652

AC:

2917

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

4193

AN:

26130

East Asian (EAS)

AF:

0.0484

AC:

1923

AN:

39696

South Asian (SAS)

AF:

0.110

AC:

9488

AN:

86256

European-Finnish (FIN)

AF:

0.0413

AC:

2206

AN:

53420

Middle Eastern (MID)

AF:

0.198

AC:

1141

AN:

5768

European-Non Finnish (NFE)

AF:

0.101

AC:

112728

AN:

1111752

Other (OTH)

AF:

0.105

AC:

6365

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

6877

13754

20632

27509

34386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4020

8040

12060

16080

20100

<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:

0.0781

AC:

11883

AN:

152192

Hom.:

547

Cov.:

AF XY:

0.0757

AC XY:

5630

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0361

AC:

1500

AN:

41550

American (AMR)

AF:

0.0843

AC:

1287

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

523

AN:

3466

East Asian (EAS)

AF:

0.0481

AC:

249

AN:

5180

South Asian (SAS)

AF:

0.116

AC:

557

AN:

4816

European-Finnish (FIN)

AF:

0.0358

AC:

379

AN:

10598

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

7017

AN:

67994

Other (OTH)

AF:

0.0970

AC:

205

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

566

1132

1697

2263

2829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.100

Hom.:

4001

Bravo

AF:

0.0806

Asia WGS

AF:

0.0770

AC:

266

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.116

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0546

AC:

6704

AN:

122682

Turkish Variome

AF:

0.158

AC:

1063

AN:

6722

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0426

AC:

382

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0978

AC:

229

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cholangiocarcinoma (1)

Triple-negative breast cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Benign

-0.080

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.20

PhyloP100

2.8

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.25

Sift

Benign

0.15

Sift4G

Benign

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.27

Mutation Taster

=99/1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over