14-61721514-T-G

Variant names:

• chr14-61721514-T-G
• rs1325730250
• NM_001530.4:c.232T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001530.4(HIF1A):​c.232T>G​(p.Leu78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HIF1A NM_001530.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400

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:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1294682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.232T>G	p.Leu78Val	missense_variant	Exon 3 of 15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.304T>G	p.Leu102Val	missense_variant	Exon 3 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.232T>G	p.Leu78Val	missense_variant	Exon 3 of 14		NP_851397.1
HIF1A-AS3	NR_144368.1	n.214-4497A>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.232T>G	p.Leu78Val	missense_variant	Exon 3 of 15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T;T;.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T;T;D;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L;.;L;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.070	N;N;N;N;N
REVEL	Benign	0.083
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.29	B;B;.;.;.
Vest4		0.25
MutPred		0.47		.;Loss of helix (P = 0.1299);.;.;.;
MVP		0.64
MPC		0.75
ClinPred		0.12	T
GERP RS		0.096
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.032
gMVP		0.19

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: rs1325730250; hg19: chr14-62188232;