dbSNP rs3826795: HIF3A:c.26+74G>A (chr19-46297176-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_152795.4(HIF3A):c.26+74G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 634,342 control chromosomes in the GnomAD database, including 13,522 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 0.21 ( 3256 hom., cov: 27)

Exomes 𝑓: 0.15 ( 10266 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

30201

AN:

147348

Hom.:

3243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.276

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.303

Gnomad EAS

AF:

0.485

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.260

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.240

GnomAD4 exome

AF:

0.146

AC:

71296

AN:

486876

Hom.:

10266

AF XY:

0.153

AC XY:

37374

AN XY:

243672

show subpopulations

African (AFR)

AF:

0.0891

AC:

1144

AN:

12834

American (AMR)

AF:

0.327

AC:

4575

AN:

14006

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

2743

AN:

9486

East Asian (EAS)

AF:

0.550

AC:

12507

AN:

22758

South Asian (SAS)

AF:

0.249

AC:

3122

AN:

12536

European-Finnish (FIN)

AF:

0.145

AC:

3921

AN:

27126

Middle Eastern (MID)

AF:

0.242

AC:

629

AN:

2596

European-Non Finnish (NFE)

AF:

0.107

AC:

38709

AN:

363240

Other (OTH)

AF:

0.177

AC:

3946

AN:

22294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

2362

4724

7086

9448

11810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

606

1212

1818

2424

3030

<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:

0.205

AC:

30239

AN:

147466

Hom.:

3256

Cov.:

AF XY:

0.208

AC XY:

14935

AN XY:

71818

show subpopulations

African (AFR)

AF:

0.138

AC:

5609

AN:

40566

American (AMR)

AF:

0.310

AC:

4400

AN:

14198

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

1038

AN:

3422

East Asian (EAS)

AF:

0.486

AC:

2133

AN:

4392

South Asian (SAS)

AF:

0.305

AC:

1411

AN:

4624

European-Finnish (FIN)

AF:

0.138

AC:

1424

AN:

10294

Middle Eastern (MID)

AF:

0.253

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.201

AC:

13417

AN:

66806

Other (OTH)

AF:

0.246

AC:

498

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1013

2025

3038

4050

5063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<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:

0.214

Hom.:

11631

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.7

(source)

DANN

Benign

0.61

PhyloP100

0.14

PromoterAI

0.0080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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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