rs1957757

Variant names:

• chr14-61730230-T-C
• rs1957757
• NM_001530.4:c.774-2188T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001530.4(HIF1A):​c.774-2188T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 152,094 control chromosomes in the GnomAD database, including 46,913 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 0.74 (46913 hom., cov: 31)
• Consequence: HIF1A NM_001530.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 24 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-AS3 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.774-2188T>C		intron_variant	Intron 6 of 14	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.846-2188T>C		intron_variant	Intron 6 of 14		NP_001230013.1
HIF1A	NM_181054.3	c.774-2188T>C		intron_variant	Intron 6 of 13		NP_851397.1
HIF1A-AS3	NR_144368.1	n.214-13213A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.774-2188T>C		intron_variant	Intron 6 of 14	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112812 AN: 151976 Hom.: 46894 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.964

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.766

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

GnomAD4 genome AF: 0.742 AC: 112876 AN: 152094 Hom.: 46913 Cov.: 31 AF XY: 0.747 AC XY: 55551 AN XY: 74334

African (AFR) AF: 0.332 AC: 13755 AN: 41432

American (AMR) AF: 0.849 AC: 12979 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 2848 AN: 3472

East Asian (EAS) AF: 0.832 AC: 4303 AN: 5170

South Asian (SAS) AF: 0.785 AC: 3786 AN: 4822

European-Finnish (FIN) AF: 0.956 AC: 10136 AN: 10604

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.917 AC: 62337 AN: 67986

Other (OTH) AF: 0.769 AC: 1625 AN: 2114

Alfa AF: 0.865 Hom.: 96410

Bravo AF: 0.719

Asia WGS AF: 0.800 AC: 2781 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.85
DANN	Benign	0.69
PhyloP100		-1.3
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: rs1957757; hg19: chr14-62196948;