Genetic Variant NM_001530.4:c.2386A>G (chr14-61746990-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001530.4(HIF1A):c.2386A>G(p.Thr796Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.72

Publications

4 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:

HIF1A-AS2 (HGNC:43015): (HIF1A antisense RNA 2)

HIF1A-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

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.2386A>G	p.Thr796Ala	missense	Exon 15 of 15	NP_001521.1	D0VY79
HIF1A	NM_001243084.2		c.2458A>G	p.Thr820Ala	missense	Exon 15 of 15	NP_001230013.1	Q16665-3
HIF1A	NM_181054.3		c.*51A>G		3_prime_UTR	Exon 14 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.2386A>G	p.Thr796Ala	missense	Exon 15 of 15	ENSP00000338018.4	Q16665-1
HIF1A	ENST00000539097.2	TSL:1	c.2458A>G	p.Thr820Ala	missense	Exon 15 of 15	ENSP00000437955.1	Q16665-3
HIF1A	ENST00000394997.5	TSL:1	c.2389A>G	p.Thr797Ala	missense	Exon 15 of 15	ENSP00000378446.1	A8MYV6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.0036

MutationAssessor

Uncertain

2.6

PhyloP100

8.7

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.55

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.77

MutPred

0.47

Loss of disorder (P = 0.2495)

MVP

0.76

MPC

0.57

ClinPred

0.97

GERP RS

5.7

Varity_R

0.72

gMVP

0.66

Mutation Taster

=19/81

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over