14-61732415-C-T

Variant names:

• chr14-61732415-C-T
• rs200037213
• NM_001530.4:c.774-3C>T

Variant summary

Our verdict is Benign. The variant received -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, 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, 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:):

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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.774-3C>T		splice_region_variant, intron_variant	Intron 6 of 14	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.846-3C>T		splice_region_variant, intron_variant	Intron 6 of 14		NP_001230013.1
HIF1A	NM_181054.3	c.774-3C>T		splice_region_variant, intron_variant	Intron 6 of 13		NP_851397.1
HIF1A-AS3	NR_144368.1	n.214-15398G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.774-3C>T		splice_region_variant, intron_variant	Intron 6 of 14	1	NM_001530.4	ENSP00000338018.4

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

GnomAD2 exomes AF: 0.00134 AC: 328 AN: 244848 AF XY: 0.00140

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 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 AC: 6 AN: 32498

Gnomad4 AMR exome AF: 0.000486 AC: 21 AN: 43190

Gnomad4 ASJ exome AF: 0.0000389 AC: 1 AN: 25710

Gnomad4 EAS exome AF: 0.0000254 AC: 1 AN: 39420

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83700

Gnomad4 FIN exome AF: 0.00115 AC: 61 AN: 53078

Gnomad4 NFE exome AF: 0.00216 AC: 2338 AN: 1083986

Gnomad4 Remaining exome AF: 0.00107 AC: 63 AN: 59150

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 AC: 0.000506097 AN: 0.000506097

Gnomad4 AMR AF: 0.00151 AC: 0.00150602 AN: 0.00150602

Gnomad4 ASJ AF: 0.000288 AC: 0.000288184 AN: 0.000288184

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00142 AC: 0.00142477 AN: 0.00142477

Gnomad4 NFE AF: 0.00175 AC: 0.00175021 AN: 0.00175021

Gnomad4 OTH AF: 0.00142 AC: 0.00142045 AN: 0.00142045

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

Mar 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
Mutation Taster		=100/0	polymorphism

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;