rs11549467

Positions:

chr14-61740857-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001530.4(HIF1A):c.1762G>A(p.Ala588Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00783 in 1,614,010 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0074 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 98 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.25

Variant links:

Genes affected

HIF1A (HGNC:4910): (hypoxia inducible factor 1 subunit alpha) This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2011]

HIF1A links:

HIF1A (HGNC:):

HIF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013724267).

BP6

Variant 14-61740857-G-A is Benign according to our data. Variant chr14-61740857-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2683253.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00737 (1121/152172) while in subpopulation EAS AF= 0.0398 (206/5180). AF 95% confidence interval is 0.0353. There are 11 homozygotes in gnomad4. There are 583 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1121 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIF1A	NM_001530.4 linkuse as main transcript	c.1762G>A	p.Ala588Thr	missense_variant	12/15	ENST00000337138.9	NP_001521.1	Q16665-1D0VY79
HIF1A	NM_001243084.2 linkuse as main transcript	c.1834G>A	p.Ala612Thr	missense_variant	12/15		NP_001230013.1	Q16665-3
HIF1A	NM_181054.3 linkuse as main transcript	c.1762G>A	p.Ala588Thr	missense_variant	12/14		NP_851397.1	Q16665-2
HIF1A-AS3	NR_144368.1 linkuse as main transcript	n.213+10028C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9 linkuse as main transcript	c.1762G>A	p.Ala588Thr	missense_variant	12/15	1	NM_001530.4	ENSP00000338018.4		Q16665-1

Frequencies

GnomAD3 genomes

AF:

0.00737

AC:

1121

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0397

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00939

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00891

AC:

2240

AN:

251486

Hom.:

AF XY:

0.00876

AC XY:

1190

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.0368

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.00894

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.00787

AC:

11510

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00802

AC XY:

5834

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00494

Gnomad4 EAS exome

AF:

0.0416

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.00738

Gnomad4 OTH exome

AF:

0.00647

GnomAD4 genome

AF:

0.00737

AC:

1121

AN:

152172

Hom.:

Cov.:

AF XY:

0.00784

AC XY:

583

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00151

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.0398

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0160

Gnomad4 NFE

AF:

0.00940

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00828

Hom.:

Bravo

AF:

0.00557

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.00974

AC:

1183

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00649

EpiControl

AF:

0.00646

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2023	BS2, BP4_strong, PS3_supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.79

DANN

Benign

0.80

DEOGEN2

Benign

0.32

T;T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.73

T;T;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

N;.;N;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.16

N;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.37

T;T;T;T;T

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.030

MVP

0.24

MPC

0.12

ClinPred

0.0023

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.033

gMVP

0.069

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over