rs41508050

Positions:

• chr14-61738090-C-A
• chr14-61738090-C-T

Variant summary

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

The NM_001530.4(HIF1A):​c.1253C>A​(p.Thr418Lys) 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. 16/21 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: 32)
• Consequence: HIF1A NM_001530.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51

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 (HGNC:):

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=0.16653273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.1253C>A	p.Thr418Lys	missense_variant	10/15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.1325C>A	p.Thr442Lys	missense_variant	10/15		NP_001230013.1
HIF1A	NM_181054.3	c.1253C>A	p.Thr418Lys	missense_variant	10/14		NP_851397.1
HIF1A-AS3	NR_144368.1	n.213+12795G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.1253C>A	p.Thr418Lys	missense_variant	10/15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;T;.;T;.
Eigen	Benign	-0.069
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.52	N;N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.035	D;D;D;D;D
Sift4G	Benign	0.91	T;T;T;T;T
Polyphen		0.019	B;B;.;.;.
Vest4		0.31
MutPred		0.38		.;Gain of ubiquitination at T419 (P = 0.0018);.;.;.;
MVP		0.54
MPC		1.0
ClinPred		0.42	T
GERP RS		5.6
Varity_R		0.059
gMVP		0.29

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: rs41508050; hg19: chr14-62204808;