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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF3A	NM_152795.4	MANE Select	c.26+74G>A		intron	N/A	NP_690008.2	Q9Y2N7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HIF3A	ENST00000377670.9	TSL:1 MANE Select	c.26+74G>A	intron	N/A	ENSP00000366898.3	Q9Y2N7-1
HIF3A	ENST00000244302.8	TSL:1	n.57+74G>A	intron	N/A
HIF3A	ENST00000475432.6	TSL:1	n.57+74G>A	intron	N/A

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over