rs11549465

Positions:

• chr14-61740839-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 2.79

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)

ACMG classification

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	UniProt
HIF1A	NM_001530.4	c.1744C>T	p.Pro582Ser	missense_variant	12/15	ENST00000337138.9	NP_001521.1
HIF1A-AS3	NR_144368.1	n.213+10046G>A		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.1816C>T	p.Pro606Ser	missense_variant	12/15		NP_001230013.1
HIF1A	NM_181054.3	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	c.1744C>T	p.Pro582Ser	missense_variant	12/15	1	NM_001530.4	ENSP00000338018	P4
HIF1A-AS3	ENST00000660325.2	n.215+10046G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11893 AN: 152074 Hom.: 548 Cov.: 32

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

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

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

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:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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	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

Other links and lift over

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