rs2295778

Variant names:

• chr10-100536079-C-G
• rs2295778
• NM_017902.3:c.121C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-100536079-C-G
• chr10-100536079-C-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict 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 (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
• Publications: 40 publications found

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

Our verdict: Benign. The variant received -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	c.121C>G	p.Pro41Ala	missense_variant	Exon 1 of 8	ENST00000299163.7	NP_060372.2
HIF1AN	XM_011539940.3	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	Appris	UniProt
HIF1AN	ENST00000299163.7	c.121C>G	p.Pro41Ala	missense_variant	Exon 1 of 8	1	NM_017902.3	ENSP00000299163.4
HIF1AN	ENST00000533589.6	c.-144-332C>G		intron_variant	Intron 1 of 5	3		ENSP00000433360.2
HIF1AN	ENST00000526476.5	n.92+29C>G		intron_variant	Intron 1 of 4	3		ENSP00000432791.1
HIF1AN	ENST00000528044.1	n.-119C>G		upstream_gene_variant		4

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

GnomAD2 exomes AF: 0.245 AC: 60411 AN: 246292 AF XY: 0.250

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 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

African (AFR) AF: 0.0452 AC: 1510 AN: 33432

American (AMR) AF: 0.210 AC: 9310 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 9350 AN: 26080

East Asian (EAS) AF: 0.249 AC: 9864 AN: 39658

South Asian (SAS) AF: 0.253 AC: 21731 AN: 86028

European-Finnish (FIN) AF: 0.236 AC: 12399 AN: 52644

Middle Eastern (MID) AF: 0.248 AC: 1429 AN: 5760

European-Non Finnish (NFE) AF: 0.275 AC: 304992 AN: 1110760

Other (OTH) AF: 0.261 AC: 15744 AN: 60288

GnomAD4 genome AF: 0.205 AC: 31184 AN: 151920 Hom.: 4008 Cov.: 30 AF XY: 0.205 AC XY: 15189 AN XY: 74244

African (AFR) AF: 0.0544 AC: 2259 AN: 41506

American (AMR) AF: 0.212 AC: 3238 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3466

East Asian (EAS) AF: 0.246 AC: 1264 AN: 5138

South Asian (SAS) AF: 0.238 AC: 1142 AN: 4798

European-Finnish (FIN) AF: 0.248 AC: 2618 AN: 10536

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18579 AN: 67896

Other (OTH) AF: 0.214 AC: 451 AN: 2112

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
PhyloP100		3.1
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
PromoterAI		-0.22	Neutral
Varity_R		0.28
gMVP		0.41
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

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