14-61747130-T-C

Variant names:

• chr14-61747130-T-C
• rs2057482
• NM_001530.4:c.*45T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001530.4(HIF1A):​c.*45T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,548,668 control chromosomes in the GnomAD database, including 554,863 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 0.80 (49554 hom., cov: 32)
  • Exomes 𝑓: 0.85 (505309 hom.)
• Consequence: HIF1A NM_001530.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54

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

HIF1A-AS3 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.*45T>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000337138.9	NP_001521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.*45T>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121899 AN: 152030 Hom.: 49532 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.848

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.940

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.800

GnomAD2 exomes AF: 0.835 AC: 177949 AN: 213048 AF XY: 0.832

Gnomad AFR exome AF: 0.663

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.756

Gnomad EAS exome AF: 0.805

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.856

Gnomad OTH exome AF: 0.838

GnomAD4 exome AF: 0.849 AC: 1185326 AN: 1396518 Hom.: 505309 Cov.: 22 AF XY: 0.846 AC XY: 587767 AN XY: 694830

Gnomad4 AFR exome AF: 0.657 AC: 20362 AN: 30994

Gnomad4 AMR exome AF: 0.894 AC: 31722 AN: 35486

Gnomad4 ASJ exome AF: 0.757 AC: 17361 AN: 22920

Gnomad4 EAS exome AF: 0.809 AC: 31747 AN: 39266

Gnomad4 SAS exome AF: 0.745 AC: 57975 AN: 77846

Gnomad4 FIN exome AF: 0.933 AC: 48380 AN: 51880

Gnomad4 NFE exome AF: 0.862 AC: 926510 AN: 1074930

Gnomad4 Remaining exome AF: 0.823 AC: 47492 AN: 57720

GnomAD4 genome AF: 0.802 AC: 121974 AN: 152150 Hom.: 49554 Cov.: 32 AF XY: 0.804 AC XY: 59798 AN XY: 74382

Gnomad4 AFR AF: 0.664 AC: 0.664133 AN: 0.664133

Gnomad4 AMR AF: 0.849 AC: 0.84862 AN: 0.84862

Gnomad4 ASJ AF: 0.750 AC: 0.750288 AN: 0.750288

Gnomad4 EAS AF: 0.807 AC: 0.80652 AN: 0.80652

Gnomad4 SAS AF: 0.733 AC: 0.733499 AN: 0.733499

Gnomad4 FIN AF: 0.940 AC: 0.940083 AN: 0.940083

Gnomad4 NFE AF: 0.860 AC: 0.860087 AN: 0.860087

Gnomad4 OTH AF: 0.802 AC: 0.802271 AN: 0.802271

Alfa AF: 0.834 Hom.: 217019

Bravo AF: 0.790

Asia WGS AF: 0.778 AC: 2706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=100/0	polymorphism (auto)

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

LitVar

Other links and lift over

dbSNP: rs2057482; hg19: chr14-62213848; COSMIC: COSV60189685;