14-61741287-T-G

Variant names:

• chr14-61741287-T-G
• rs4902080
• NM_001530.4:c.2093+99T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001530.4(HIF1A):​c.2093+99T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000031 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HIF1A NM_001530.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 10 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	NM_001530.4	MANE Select	c.2093+99T>G		intron	N/A	NP_001521.1
	HIF1A	NM_001243084.2		c.2165+99T>G		intron	N/A	NP_001230013.1
	HIF1A	NM_181054.3		c.2093+99T>G		intron	N/A	NP_851397.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.2093+99T>G		intron	N/A	ENSP00000338018.4
	HIF1A	ENST00000539097.2	TSL:1	c.2165+99T>G		intron	N/A	ENSP00000437955.1
	HIF1A	ENST00000394997.5	TSL:1	c.2096+99T>G		intron	N/A	ENSP00000378446.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000306 AC: 2 AN: 652556 Hom.: 0 AF XY: 0.00000595 AC XY: 2 AN XY: 336406

African (AFR) AF: 0.00 AC: 0 AN: 15676

American (AMR) AF: 0.00 AC: 0 AN: 19218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14978

East Asian (EAS) AF: 0.00 AC: 0 AN: 32042

South Asian (SAS) AF: 0.00 AC: 0 AN: 45848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00000449 AC: 2 AN: 445068

Other (OTH) AF: 0.00 AC: 0 AN: 32366

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 79371

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.31
DANN	Benign	0.66
PhyloP100		-1.2

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: rs4902080; hg19: chr14-62208005;