rs12461322

Positions:

• chr19-46312053-G-A
• chr19-46312053-G-C

Variant summary

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

The NM_152795.4(HIF3A):​c.771-108G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 840,490 control chromosomes in the GnomAD database, including 9,085 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 0.10 (1213 hom., cov: 31)
  • Exomes 𝑓: 0.13 (7872 hom.)
• Consequence: HIF3A NM_152795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469

Genes affected

HIF3A (HGNC:15825): (hypoxia inducible factor 3 subunit alpha) The protein encoded by this gene is the alpha-3 subunit of one of several alpha/beta-subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia). The alpha-3 subunit lacks the transactivation domain found in factors containing either the alpha-1 or alpha-2 subunits. It is thought that factors containing the alpha-3 subunit are negative regulators of hypoxia-inducible gene expression. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIF3A	NM_152795.4	c.771-108G>A		intron_variant		ENST00000377670.9	NP_690008.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIF3A	ENST00000377670.9	c.771-108G>A		intron_variant		1	NM_152795.4	ENSP00000366898	P4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15348 AN: 151704 Hom.: 1212 Cov.: 31

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.142 AC: 35333 AN: 248270 Hom.: 3404 AF XY: 0.138 AC XY: 18626 AN XY: 134540

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.0740

Gnomad NFE exome AF: 0.0983

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.130 AC: 89825 AN: 688668 Hom.: 7872 Cov.: 9 AF XY: 0.130 AC XY: 48159 AN XY: 371542

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.0715

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.101 AC: 15358 AN: 151822 Hom.: 1213 Cov.: 31 AF XY: 0.105 AC XY: 7799 AN XY: 74208

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.0696

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.133

Alfa AF: 0.112 Hom.: 2258

Bravo AF: 0.111

Asia WGS AF: 0.221 AC: 770 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.55

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: rs12461322; hg19: chr19-46815310; COSMIC: COSV52199745; COSMIC: COSV52199745;