14-61722813-T-C

Variant names:

• chr14-61722813-T-C
• rs4899056
• NM_001530.4:c.457+990T>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.457+990T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 152,220 control chromosomes in the GnomAD database, including 44,698 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 0.71 (44698 hom., cov: 33)
• Consequence: HIF1A NM_001530.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• Publications: 15 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]

ENSG00000258667 (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=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	NM_001530.4	MANE Select	c.457+990T>C		intron	N/A	NP_001521.1	D0VY79
	HIF1A	NM_001243084.2		c.529+990T>C		intron	N/A	NP_001230013.1	Q16665-3
	HIF1A	NM_181054.3		c.457+990T>C		intron	N/A	NP_851397.1	Q16665-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.457+990T>C		intron	N/A	ENSP00000338018.4	Q16665-1
	HIF1A	ENST00000539097.2	TSL:1	c.529+990T>C		intron	N/A	ENSP00000437955.1	Q16665-3
	HIF1A	ENST00000394997.5	TSL:1	c.460+990T>C		intron	N/A	ENSP00000378446.1	A8MYV6

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108576 AN: 152102 Hom.: 44694 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.826

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.953

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.736

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

GnomAD4 genome AF: 0.714 AC: 108609 AN: 152220 Hom.: 44698 Cov.: 33 AF XY: 0.720 AC XY: 53551 AN XY: 74418

African (AFR) AF: 0.267 AC: 11061 AN: 41486

American (AMR) AF: 0.828 AC: 12675 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2774 AN: 3472

East Asian (EAS) AF: 0.827 AC: 4284 AN: 5182

South Asian (SAS) AF: 0.773 AC: 3729 AN: 4824

European-Finnish (FIN) AF: 0.953 AC: 10112 AN: 10614

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61377 AN: 68022

Other (OTH) AF: 0.738 AC: 1560 AN: 2114

Alfa AF: 0.839 Hom.: 81824

Bravo AF: 0.688

Asia WGS AF: 0.782 AC: 2708 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		1.8
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: rs4899056; hg19: chr14-62189531;