14-61720408-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001530.4(HIF1A):c.62A>G(p.Lys21Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HIF1A NM_001530.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3852623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIF1A	NM_001530.4	c.62A>G	p.Lys21Arg	missense_variant	2/15	ENST00000337138.9
HIF1A-AS3	NR_144368.1	n.214-3391T>C		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.134A>G	p.Lys45Arg	missense_variant	2/15
HIF1A	NM_181054.3	c.62A>G	p.Lys21Arg	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1A	ENST00000337138.9	c.62A>G	p.Lys21Arg	missense_variant	2/15	1	NM_001530.4	P4
HIF1A-AS3	ENST00000660325.2	n.216-6406T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.62A>G (p.K21R) alteration is located in exon 2 (coding exon 2) of the HIF1A gene. This alteration results from a A to G substitution at nucleotide position 62, causing the lysine (K) at amino acid position 21 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.52
MutPred		0.17		.;Loss of ubiquitination at K22 (P = 0.0341);.;.;
MVP		0.75
MPC		0.86
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.28

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: rs1461259695; hg19: chr14-62187126;