14-61747130-T-C

Variant names:

• chr14-61747130-T-C
• rs2057482
• ENST00000557538.5:n.2827T>C

Variant summary

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

The ENST00000557538.5(HIF1A):​n.2827T>C variant causes a non coding transcript exon 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 ENST00000557538.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• Publications: 86 publications found

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557538.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	NM_001530.4	MANE Select	c.*45T>C		3_prime_UTR	Exon 15 of 15	NP_001521.1
	HIF1A-AS2	NR_045406.1		n.1960A>G		non_coding_transcript_exon	Exon 1 of 1
	HIF1A	NM_001243084.2		c.*45T>C		3_prime_UTR	Exon 15 of 15	NP_001230013.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	ENST00000557538.5	TSL:1	n.2827T>C		non_coding_transcript_exon	Exon 15 of 15
	HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.*45T>C		3_prime_UTR	Exon 15 of 15	ENSP00000338018.4
	HIF1A	ENST00000539097.2	TSL:1	c.*45T>C		3_prime_UTR	Exon 15 of 15	ENSP00000437955.1

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

African (AFR) AF: 0.657 AC: 20362 AN: 30994

American (AMR) AF: 0.894 AC: 31722 AN: 35486

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 17361 AN: 22920

East Asian (EAS) AF: 0.809 AC: 31747 AN: 39266

South Asian (SAS) AF: 0.745 AC: 57975 AN: 77846

European-Finnish (FIN) AF: 0.933 AC: 48380 AN: 51880

Middle Eastern (MID) AF: 0.690 AC: 3777 AN: 5476

European-Non Finnish (NFE) AF: 0.862 AC: 926510 AN: 1074930

Other (OTH) 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

African (AFR) AF: 0.664 AC: 27527 AN: 41448

American (AMR) AF: 0.849 AC: 12972 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2602 AN: 3468

East Asian (EAS) AF: 0.807 AC: 4181 AN: 5184

South Asian (SAS) AF: 0.733 AC: 3534 AN: 4818

European-Finnish (FIN) AF: 0.940 AC: 9963 AN: 10598

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58510 AN: 68028

Other (OTH) AF: 0.802 AC: 1696 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.92
PhyloP100		3.5
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

Other links and lift over

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