rs4902080

Positions:

• chr14-61741287-T-C
• chr14-61741287-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000337138.9(HIF1A):​c.2093+99T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 804,300 control chromosomes in the GnomAD database, including 348,015 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 0.87 (58482 hom., cov: 31)
  • Exomes 𝑓: 0.94 (289533 hom.)
• Consequence: HIF1A ENST00000337138.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18

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:54284): (HIF1A antisense RNA 3)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.2093+99T>C		intron_variant		ENST00000337138.9	NP_001521.1
HIF1A-AS3	NR_144368.1	n.213+9598A>G		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.2165+99T>C		intron_variant			NP_001230013.1
HIF1A	NM_181054.3	c.2093+99T>C		intron_variant			NP_851397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.2093+99T>C		intron_variant		1	NM_001530.4	ENSP00000338018	P4
HIF1A-AS3	ENST00000660325.2	n.215+9598A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.868 AC: 131751 AN: 151860 Hom.: 58473 Cov.: 31

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.978

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.975

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.882

GnomAD4 exome AF: 0.940 AC: 613247 AN: 652326 Hom.: 289533 AF XY: 0.938 AC XY: 315373 AN XY: 336276

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.949

Gnomad4 ASJ exome AF: 0.917

Gnomad4 EAS exome AF: 0.856

Gnomad4 SAS exome AF: 0.852

Gnomad4 FIN exome AF: 0.973

Gnomad4 NFE exome AF: 0.964

Gnomad4 OTH exome AF: 0.923

GnomAD4 genome AF: 0.867 AC: 131808 AN: 151974 Hom.: 58482 Cov.: 31 AF XY: 0.867 AC XY: 64409 AN XY: 74276

Gnomad4 AFR AF: 0.659

Gnomad4 AMR AF: 0.928

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 0.849

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.975

Gnomad4 NFE AF: 0.963

Gnomad4 OTH AF: 0.883

Alfa AF: 0.946 Hom.: 61112

Bravo AF: 0.857

Asia WGS AF: 0.850 AC: 2953 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.38
DANN	Benign	0.67

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: rs4902080; hg19: chr14-62208005;