19-46312053-G-T

Variant names:

• chr19-46312053-G-T
• rs12461322
• NM_152795.4:c.771-108G>T

Variant summary

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

The NM_152795.4(HIF3A):​c.771-108G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 688,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000029 (0 hom.)
• Consequence: HIF3A NM_152795.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469
• Publications: 0 publications found

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

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=-0.94).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152795.4. 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
	HIF3A	NM_152795.4	MANE Select	c.771-108G>T		intron	N/A	NP_690008.2
	HIF3A	NM_152794.4		c.765-108G>T		intron	N/A	NP_690007.1
	HIF3A	NM_022462.4		c.564-108G>T		intron	N/A	NP_071907.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF3A	ENST00000377670.9	TSL:1 MANE Select	c.771-108G>T		intron	N/A	ENSP00000366898.3
	HIF3A	ENST00000300862.7	TSL:1	c.765-108G>T		intron	N/A	ENSP00000300862.3
	HIF3A	ENST00000244302.8	TSL:1	n.802-108G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000290 AC: 2 AN: 688846 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 371650

⚠️ 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: 18782

American (AMR) AF: 0.00 AC: 0 AN: 43778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21398

East Asian (EAS) AF: 0.00 AC: 0 AN: 36322

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 408340

Other (OTH) AF: 0.0000285 AC: 1 AN: 35060

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.71
DANN	Benign	0.58
PhyloP100		-0.47

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: rs12461322; hg19: chr19-46815310;