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rs11549465

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. 11/19 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: đť‘“ 0.078 ( 547 hom., cov: 32)
Exomes đť‘“: 0.097 ( 7416 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

6
12

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

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: {Uncertain_significance=1, Benign=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 UniProt
HIF1ANM_001530.4 linkuse as main transcriptc.1744C>T p.Pro582Ser missense_variant 12/15 ENST00000337138.9
HIF1A-AS3NR_144368.1 linkuse as main transcriptn.213+10046G>A intron_variant, non_coding_transcript_variant
HIF1ANM_001243084.2 linkuse as main transcriptc.1816C>T p.Pro606Ser missense_variant 12/15
HIF1ANM_181054.3 linkuse as main transcriptc.1744C>T p.Pro582Ser missense_variant 12/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HIF1AENST00000337138.9 linkuse as main transcriptc.1744C>T p.Pro582Ser missense_variant 12/151 NM_001530.4 P4Q16665-1
HIF1A-AS3ENST00000660325.2 linkuse as main transcriptn.215+10046G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0782
AC:
11893
AN:
152074
Hom.:
548
Cov.:
32
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.:
32
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.:
32
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
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 25, 2023BS1, BP4 -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Cholangiocarcinoma Other:1
other, no assertion criteria providedresearchDepartment of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin BerlinDec 10, 2022No 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
T
BayesDel_noAF
Benign
-0.39
Cadd
Benign
19
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
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
MetaRNN
Benign
0.0020
T;T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.20
N;.;N;.;.
MutationTaster
Benign
0.0044
P;P;P;P;P
PrimateAI
Uncertain
0.61
T
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
T
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.

Other links and lift over

dbSNP: rs11549465; hg19: chr14-62207557; COSMIC: COSV60188026; COSMIC: COSV60188026; API