Genetic Variant HIF3A:c.26+74G>T (chr19-46297176-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152795.4(HIF3A):c.26+74G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 634,964 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: 𝑓 0.000034 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

HIF3A
NM_152795.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.137

Publications

24 publications found

Variant links:

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]

HIF3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF3A	NM_152795.4 link	c.26+74G>T		intron_variant	Intron 1 of 14	ENST00000377670.9	NP_690008.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
HIF3A	ENST00000377670.9 link	c.26+74G>T	intron_variant	Intron 1 of 14	1	NM_152795.4	ENSP00000366898.3
HIF3A	ENST00000244302.8 link	n.57+74G>T	intron_variant	Intron 1 of 12	1
HIF3A	ENST00000475432.6 link	n.57+74G>T	intron_variant	Intron 1 of 6	1
HIF3A	ENST00000533789.5 link	n.26+74G>T	intron_variant	Intron 1 of 4	4		ENSP00000432809.1

Frequencies

GnomAD3 genomes

AF:

0.0000339

AC:

AN:

147616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000598

Gnomad OTH

AF:

0.000500

GnomAD4 exome

AF:

0.0000103

AC:

AN:

487348

Hom.:

AF XY:

0.00000410

AC XY:

AN XY:

243918

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

12844

American (AMR)

AF:

0.0000712

AC:

AN:

14040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9506

East Asian (EAS)

AF:

0.00

AC:

AN:

22820

South Asian (SAS)

AF:

0.00

AC:

AN:

12554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2606

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

363510

Other (OTH)

AF:

0.00

AC:

AN:

22308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0632148), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000339

AC:

AN:

147616

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

71810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40514

American (AMR)

AF:

0.00

AC:

AN:

14208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

4414

South Asian (SAS)

AF:

0.00

AC:

AN:

4644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000598

AC:

AN:

66928

Other (OTH)

AF:

0.000500

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

11631

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.2

(source)

DANN

Benign

0.32

PhyloP100

0.14

PromoterAI

0.013

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over