rs12434438

Positions:

• chr14-61730580-G-A
• chr14-61730580-G-C

Variant summary

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

The NM_001530.4(HIF1A):​c.774-1838G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 152,084 control chromosomes in the GnomAD database, including 35,265 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 0.64 (35265 hom., cov: 32)
• Consequence: HIF1A NM_001530.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.699

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.774-1838G>A		intron_variant		ENST00000337138.9	NP_001521.1
HIF1A-AS3	NR_144368.1	n.214-13563C>T		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.846-1838G>A		intron_variant			NP_001230013.1
HIF1A	NM_181054.3	c.774-1838G>A		intron_variant			NP_851397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.774-1838G>A		intron_variant		1	NM_001530.4	ENSP00000338018	P4
HIF1A-AS3	ENST00000660325.2	n.216-16578C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96570 AN: 151966 Hom.: 35249 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.629

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

GnomAD4 genome AF: 0.635 AC: 96623 AN: 152084 Hom.: 35265 Cov.: 32 AF XY: 0.644 AC XY: 47886 AN XY: 74338

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.736

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.779

Gnomad4 SAS AF: 0.655

Gnomad4 FIN AF: 0.909

Gnomad4 NFE AF: 0.789

Gnomad4 OTH AF: 0.634

Alfa AF: 0.749 Hom.: 82343

Bravo AF: 0.608

Asia WGS AF: 0.708 AC: 2462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.5
DANN	Benign	0.61

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: rs12434438; hg19: chr14-62197298;