ENST00000557538.5:n.220_221delTT

Variant names:

• chr14-61697832-ATT-A
• rs113243889
• ENST00000557538.5:n.220_221delTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000557538.5(HIF1A):​n.220_221delTT 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 0.00000159 in 1,257,254 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: HIF1A ENST00000557538.5 non_coding_transcript_exon
• 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]

HIF1A-AS3 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.35+2002_35+2003delTT		intron_variant	Intron 1 of 14	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.-10_-9delTT		5_prime_UTR_variant	Exon 1 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.35+2002_35+2003delTT		intron_variant	Intron 1 of 13		NP_851397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.35+2002_35+2003delTT		intron_variant	Intron 1 of 14	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000443 AC: 2 AN: 45182 AF XY: 0.0000396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000568

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000159 AC: 2 AN: 1257254 Hom.: 0 AF XY: 0.00000162 AC XY: 1 AN XY: 618554

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

African (AFR) AF: 0.00 AC: 0 AN: 27220

American (AMR) AF: 0.00 AC: 0 AN: 22670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21146

East Asian (EAS) AF: 0.00 AC: 0 AN: 31908

South Asian (SAS) AF: 0.00 AC: 0 AN: 65454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5140

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 1002032

Other (OTH) AF: 0.00 AC: 0 AN: 52140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;