dbSNP rs12434438: HIF1A:c.774-1838G>A (chr14-61730580-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001530.4(HIF1A):c.774-1838G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,084 control chromosomes in the GnomAD database, including 35,265 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.64 ( 35265 hom., cov: 32)

Consequence

HIF1A
NM_001530.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.699

Publications

42 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4 link	c.774-1838G>A	intron_variant	Intron 6 of 14	ENST00000337138.9	NP_001521.1	Q16665-1D0VY79
HIF1A	NM_001243084.2 link	c.846-1838G>A	intron_variant	Intron 6 of 14		NP_001230013.1	Q16665-3
HIF1A	NM_181054.3 link	c.774-1838G>A	intron_variant	Intron 6 of 13		NP_851397.1	Q16665-2
HIF1A-AS3	NR_144368.1 link	n.214-13563C>T	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9 link	c.774-1838G>A		intron_variant	Intron 6 of 14	1	NM_001530.4	ENSP00000338018.4		Q16665-1

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96570

AN:

151966

Hom.:

35249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.822

Gnomad AMR

AF:

0.735

Gnomad ASJ

AF:

0.629

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.909

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.789

Gnomad OTH

AF:

0.629

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.635

AC:

96623

AN:

152084

Hom.:

35265

Cov.:

AF XY:

0.644

AC XY:

47886

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.253

AC:

10499

AN:

41446

American (AMR)

AF:

0.736

AC:

11240

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.629

AC:

2183

AN:

3468

East Asian (EAS)

AF:

0.779

AC:

4034

AN:

5180

South Asian (SAS)

AF:

0.655

AC:

3160

AN:

4822

European-Finnish (FIN)

AF:

0.909

AC:

9633

AN:

10594

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.789

AC:

53613

AN:

67982

Other (OTH)

AF:

0.634

AC:

1338

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1338

2676

4015

5353

6691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<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:

0.723

Hom.:

111655

Bravo

AF:

0.608

Asia WGS

AF:

0.708

AC:

2462

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

9.5

(source)

DANN

Benign

0.61

PhyloP100

0.70

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over