14-61740839-C-T

Position:

chr14-61740839-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001530.4(HIF1A):c.1744C>T(p.Pro582Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0954 in 1,613,808 control chromosomes in the GnomAD database, including 7,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.078 ( 547 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7416 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.79

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-AS3 (HGNC:54284): (HIF1A antisense RNA 3)

HIF1A-AS3 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=0.002049476).

BP6

Variant 14-61740839-C-T is Benign according to our data. Variant chr14-61740839-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2571397.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HIF1A	NM_001530.4 linkuse as main transcript	c.1744C>T	p.Pro582Ser	missense_variant	12/15	ENST00000337138.9	NP_001521.1
HIF1A-AS3	NR_144368.1 linkuse as main transcript	n.213+10046G>A		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2 linkuse as main transcript	c.1816C>T	p.Pro606Ser	missense_variant	12/15		NP_001230013.1
HIF1A	NM_181054.3 linkuse as main transcript	c.1744C>T	p.Pro582Ser	missense_variant	12/14		NP_851397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9 linkuse as main transcript	c.1744C>T	p.Pro582Ser	missense_variant	12/15	1	NM_001530.4	ENSP00000338018	P4	Q16665-1
HIF1A-AS3	ENST00000660325.2 linkuse as main transcript	n.215+10046G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0782

AC:

11893

AN:

152074

Hom.:

548

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.0845

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.0482

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0358

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.0985

GnomAD3 exomes

AF:

0.0881

AC:

22150

AN:

251470

Hom.:

1162

AF XY:

0.0928

AC XY:

12614

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.0629

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.0428

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0389

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.0973

AC:

142148

AN:

1461616

Hom.:

7416

Cov.:

AF XY:

0.0983

AC XY:

71461

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0355

Gnomad4 AMR exome

AF:

0.0652

Gnomad4 ASJ exome

AF:

0.160

Gnomad4 EAS exome

AF:

0.0484

Gnomad4 SAS exome

AF:

0.110

Gnomad4 FIN exome

AF:

0.0413

Gnomad4 NFE exome

AF:

0.101

Gnomad4 OTH exome

AF:

0.105

GnomAD4 genome

AF:

0.0781

AC:

11883

AN:

152192

Hom.:

547

Cov.:

AF XY:

0.0757

AC XY:

5630

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0361

Gnomad4 AMR

AF:

0.0843

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.0481

Gnomad4 SAS

AF:

0.116

Gnomad4 FIN

AF:

0.0358

Gnomad4 NFE

AF:

0.103

Gnomad4 OTH

AF:

0.0970

Alfa

AF:

0.105

Hom.:

2354

Bravo

AF:

0.0806

TwinsUK

AF:

0.105

AC:

390

ALSPAC

AF:

0.0968

AC:

373

ESP6500AA

AF:

0.0413

AC:

182

ESP6500EA

AF:

0.111

AC:

958

ExAC

AF:

0.0897

AC:

10886

Asia WGS

AF:

0.0770

AC:

266

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.116

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 25, 2023	BS1, BP4 -

Cholangiocarcinoma

Other:1

other, no assertion criteria provided

research

Department of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin Berlin

Dec 10, 2022

No association with disease-free or overall survival after resection of intrahepatic Cholangiocarcinoma No association with disease-free or overall survival

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;T;.;T;.

Eigen

Benign

-0.080

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D;D;D;D

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.20

N;.;N;.;.

MutationTaster

Benign

0.0044

P;P;P;P;P

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.1

D;D;D;D;D

REVEL

Benign

0.25

Sift

Benign

0.15

T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.24

B;P;.;.;.

Vest4

0.061

MPC

0.19

ClinPred

0.053

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.27

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