ENST00000539097:c.-9dupT

Variant names:

• chr14-61697832-A-AT
• rs113243889
• ENST00000539097.2:c.-9dupT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The ENST00000539097.2(HIF1A):​c.-9dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,379,122 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (1 hom.)
• Consequence: HIF1A ENST00000539097.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.274
• Publications: 0 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:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAd4 at 71 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000539097.2. 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.35+2003dupT		intron	N/A	NP_001521.1	D0VY79
	HIF1A	NM_001243084.2		c.-9dupT		5_prime_UTR	Exon 1 of 15	NP_001230013.1	Q16665-3
	HIF1A	NM_181054.3		c.35+2003dupT		intron	N/A	NP_851397.1	Q16665-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	ENST00000539097.2	TSL:1	c.-9dupT		5_prime_UTR	Exon 1 of 15	ENSP00000437955.1	Q16665-3
	HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.35+2003dupT		intron	N/A	ENSP00000338018.4	Q16665-1
	HIF1A	ENST00000394997.5	TSL:1	c.35+2003dupT		intron	N/A	ENSP00000378446.1	A8MYV6

Frequencies

GnomAD3 genomes AF: 0.000478 AC: 72 AN: 150588 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000531

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.0223 AC: 1007 AN: 45182 AF XY: 0.0221

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0253

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0213

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.00327 AC: 4019 AN: 1228418 Hom.: 1 Cov.: 29 AF XY: 0.00343 AC XY: 2074 AN XY: 603886

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00334 AC: 89 AN: 26648

American (AMR) AF: 0.0105 AC: 232 AN: 22024

Ashkenazi Jewish (ASJ) AF: 0.00611 AC: 126 AN: 20628

East Asian (EAS) AF: 0.00848 AC: 263 AN: 31016

South Asian (SAS) AF: 0.00712 AC: 450 AN: 63176

European-Finnish (FIN) AF: 0.00324 AC: 93 AN: 28682

Middle Eastern (MID) AF: 0.00772 AC: 39 AN: 5052

European-Non Finnish (NFE) AF: 0.00258 AC: 2534 AN: 980278

Other (OTH) AF: 0.00379 AC: 193 AN: 50914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000471 AC: 71 AN: 150704 Hom.: 0 Cov.: 32 AF XY: 0.000543 AC XY: 40 AN XY: 73624

African (AFR) AF: 0.000364 AC: 15 AN: 41180

American (AMR) AF: 0.000530 AC: 8 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3448

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5170

South Asian (SAS) AF: 0.00147 AC: 7 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000282 AC: 19 AN: 67470

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0108 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
Mutation Taster		=298/2	polymorphism

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: rs113243889; hg19: chr14-62164550; COSMIC: COSV104397814; COSMIC: COSV104397814;