14-61740839-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001243084.2(HIF1A):c.1816C>T(p.Pro606Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0954 in 1,613,808 control chromosomes in the GnomAD database, including 7,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.078 ( 547 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7416 hom. )

Consequence

HIF1A
NM_001243084.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.79

Publications

404 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002049476).

BP6

Variant 14-61740839-C-T is Benign according to our data. Variant chr14-61740839-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2571397.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243084.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HIF1A	NM_001530.4	MANE Select	c.1744C>T	p.Pro582Ser	missense	Exon 12 of 15	NP_001521.1
HIF1A	NM_001243084.2		c.1816C>T	p.Pro606Ser	missense	Exon 12 of 15	NP_001230013.1
HIF1A	NM_181054.3		c.1744C>T	p.Pro582Ser	missense	Exon 12 of 14	NP_851397.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.1744C>T	p.Pro582Ser	missense	Exon 12 of 15	ENSP00000338018.4
HIF1A	ENST00000539097.2	TSL:1	c.1816C>T	p.Pro606Ser	missense	Exon 12 of 15	ENSP00000437955.1
HIF1A	ENST00000394997.5	TSL:1	c.1747C>T	p.Pro583Ser	missense	Exon 12 of 15	ENSP00000378446.1

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

TwinsUK

AF:

0.105

AC:

390

ALSPAC

AF:

0.0968

AC:

373

ESP6500AA

AF:

0.0413

AC:

182

ESP6500EA

AF:

0.111

AC:

958

ExAC

AF:

0.0897

AC:

10886

Asia WGS

AF:

0.0770

AC:

266

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.116

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cholangiocarcinoma (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

Polyphen

0.24

Vest4

0.061

MPC

0.19

ClinPred

0.053

GERP RS

4.8

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over