rs2295778

chr10-100536079-C-Gchr10-100536079-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (4008 hom., cov: 30)
  • Exomes 𝑓: 0.26 (52755 hom.)
• Consequence: HIF1AN NM_017902.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08

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]

ACMG classification

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/exons	MANE	UniProt
HIF1AN	NM_017902.3	c.121C>G	p.Pro41Ala	missense_variant	1/8	ENST00000299163.7
HIF1AN	XM_011539940.3	c.121C>G	p.Pro41Ala	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1AN	ENST00000299163.7	c.121C>G	p.Pro41Ala	missense_variant	1/8	1	NM_017902.3	P1
HIF1AN	ENST00000533589.6	c.-144-332C>G		intron_variant		3
HIF1AN	ENST00000526476.5	c.92+29C>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31175 AN: 151802 Hom.: 4006 Cov.: 30

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

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.: 38 AF XY: 0.265 AC XY: 192239 AN XY: 725650

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.: 30 AF XY: 0.205 AC XY: 15189 AN XY: 74244

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	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	20
Dann	Benign	0.78
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.0031	P
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.089
Sift	Benign	0.16	T
Sift4G	Benign	0.75	T
Polyphen		0.0020	B
Vest4		0.054
MPC		0.73
ClinPred		0.038	T
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

Other links and lift over

dbSNP: rs2295778; hg19: chr10-102295836; COSMIC: COSV54499945; COSMIC: COSV54499945;