Genetic Variant HIF1AN:p.Pro41Ser (chr10-100536079-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017902.3(HIF1AN):c.121C>T(p.Pro41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 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: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HIF1AN
NM_017902.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.08

Publications

40 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1AN	NM_017902.3 link	c.121C>T	p.Pro41Ser	missense_variant	Exon 1 of 8	ENST00000299163.7	NP_060372.2
HIF1AN	XM_011539940.3 link	c.121C>T	p.Pro41Ser	missense_variant	Exon 1 of 8		XP_011538242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HIF1AN	ENST00000299163.7 link	c.121C>T	p.Pro41Ser	missense_variant	Exon 1 of 8	1	NM_017902.3	ENSP00000299163.4
HIF1AN	ENST00000533589.6 link	c.-144-332C>T		intron_variant	Intron 1 of 5	3		ENSP00000433360.2
HIF1AN	ENST00000526476.5 link	n.92+29C>T		intron_variant	Intron 1 of 4	3		ENSP00000432791.1
HIF1AN	ENST00000528044.1 link	n.-119C>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1459792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726066

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111190

Other (OTH)

AF:

0.00

AC:

AN:

60312

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

3969

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.10

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.040

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.90

PhyloP100

3.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.52

REVEL

Benign

0.090

Sift

Benign

0.19

Sift4G

Benign

0.73

Polyphen

0.017

Vest4

0.45

MutPred

0.21

Gain of phosphorylation at P41 (P = 0.0069);

MVP

0.26

MPC

0.77

ClinPred

0.58

GERP RS

4.1

PromoterAI

-0.27

Neutral

(source)

Varity_R

0.24

gMVP

0.45

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.36

Position offset: -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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over