dbSNP rs2295778: HIF1AN:p.Pro41Ala (chr10-100536079-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017902.3(HIF1AN):c.121C>G(p.Pro41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,610,990 control chromosomes in the GnomAD database, including 56,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.21 ( 4008 hom., cov: 30)

Exomes 𝑓: 0.26 ( 52755 hom. )

Consequence

HIF1AN
NM_017902.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.08

Variant links:

Genes affected

HIF1AN (HGNC:17113): (hypoxia inducible factor 1 subunit alpha inhibitor) Enables several functions, including 2-oxoglutarate-dependent dioxygenase activity; NF-kappaB binding activity; and transition metal ion binding activity. Involved in several processes, including negative regulation of Notch signaling pathway; negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; and protein hydroxylation. Located in cytosol; nucleoplasm; and perinuclear region of cytoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HIF1AN links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015530288).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1AN	NM_017902.3 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 1 of 8	ENST00000299163.7	NP_060372.2	Q9NWT6
HIF1AN	XM_011539940.3 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 1 of 8		XP_011538242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HIF1AN	ENST00000299163.7 link	c.121C>G	p.Pro41Ala	missense_variant	Exon 1 of 8	1	NM_017902.3	ENSP00000299163.4	Q9NWT6
HIF1AN	ENST00000533589.6 link	c.-144-332C>G		intron_variant	Intron 1 of 5	3		ENSP00000433360.2	E9PL41
HIF1AN	ENST00000526476.5 link	n.92+29C>G		intron_variant	Intron 1 of 4	3		ENSP00000432791.1	E9PNR8
HIF1AN	ENST00000528044.1 link	n.-119C>G		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31175

AN:

151802

Hom.:

4006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0546

Gnomad AMI

AF:

0.291

Gnomad AMR

AF:

0.212

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.248

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.274

Gnomad OTH

AF:

0.214

GnomAD3 exomes

AF:

0.245

AC:

60411

AN:

246292

Hom.:

7896

AF XY:

0.250

AC XY:

33498

AN XY:

134074

show subpopulations

Gnomad AFR exome

AF:

0.0472

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.359

Gnomad EAS exome

AF:

0.258

Gnomad SAS exome

AF:

0.253

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.271

Gnomad OTH exome

AF:

0.248

GnomAD4 exome

AF:

0.265

AC:

386329

AN:

1459070

Hom.:

52755

Cov.:

AF XY:

0.265

AC XY:

192239

AN XY:

725650

show subpopulations

Gnomad4 AFR exome

AF:

0.0452

Gnomad4 AMR exome

AF:

0.210

Gnomad4 ASJ exome

AF:

0.359

Gnomad4 EAS exome

AF:

0.249

Gnomad4 SAS exome

AF:

0.253

Gnomad4 FIN exome

AF:

0.236

Gnomad4 NFE exome

AF:

0.275

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.205

AC:

31184

AN:

151920

Hom.:

4008

Cov.:

AF XY:

0.205

AC XY:

15189

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0544

Gnomad4 AMR

AF:

0.212

Gnomad4 ASJ

AF:

0.376

Gnomad4 EAS

AF:

0.246

Gnomad4 SAS

AF:

0.238

Gnomad4 FIN

AF:

0.248

Gnomad4 NFE

AF:

0.274

Gnomad4 OTH

AF:

0.214

Alfa

AF:

0.258

Hom.:

3969

Bravo

AF:

0.197

TwinsUK

AF:

0.268

AC:

993

ALSPAC

AF:

0.265

AC:

1021

ESP6500AA

AF:

0.0497

AC:

218

ESP6500EA

AF:

0.256

AC:

2193

ExAC

AF:

0.243

AC:

29425

Asia WGS

AF:

0.199

AC:

695

AN:

3478

EpiCase

AF:

0.274

EpiControl

AF:

0.276

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.11

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.015

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.89

REVEL

Benign

0.089

Sift

Benign

0.16

Sift4G

Benign

0.75

Polyphen

0.0020

Vest4

0.054

MPC

0.73

ClinPred

0.038

GERP RS

4.1

Varity_R

0.28

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over