chr14-61720494-G-A

Variant names:

• chr14-61720494-G-A
• NM_001530.4:c.148G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001530.4(HIF1A):​c.148G>A​(p.Val50Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HIF1A NM_001530.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80

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-AS3 (HGNC:):

HIF1A-AS3 (HGNC:54284): (HIF1A antisense RNA 3)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.148G>A	p.Val50Met	missense_variant	Exon 2 of 15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.220G>A	p.Val74Met	missense_variant	Exon 2 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.148G>A	p.Val50Met	missense_variant	Exon 2 of 14		NP_851397.1
HIF1A-AS3	NR_144368.1	n.214-3477C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.148G>A	p.Val50Met	missense_variant	Exon 2 of 15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461296 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M;.;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.62
MutPred		0.30		.;Gain of disorder (P = 0.0957);.;.;
MVP		0.60
MPC		1.7
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-62187212;