14-61732415-C-T

Position:

• chr14-61732415-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The NM_001530.4(HIF1A):​c.774-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,578,296 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: HIF1A NM_001530.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001945
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.12

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-61732415-C-T is Benign according to our data. Variant chr14-61732415-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2920760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 187 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIF1A	NM_001530.4	c.774-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000337138.9
HIF1A-AS3	NR_144368.1	n.214-15398G>A		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.846-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
HIF1A	NM_181054.3	c.774-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1A	ENST00000337138.9	c.774-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001530.4	P4
HIF1A-AS3	ENST00000660325.2	n.216-18413G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00134 AC: 328 AN: 244848 Hom.: 1 AF XY: 0.00140 AC XY: 185 AN XY: 132188

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000484

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000840

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.000837

GnomAD4 exome AF: 0.00175 AC: 2491 AN: 1426224 Hom.: 3 Cov.: 25 AF XY: 0.00171 AC XY: 1217 AN XY: 711220

Gnomad4 AFR exome AF: 0.000185

Gnomad4 AMR exome AF: 0.000486

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00115

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74314

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00108

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.14
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: rs200037213; hg19: chr14-62199133;