chr14-61732415-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
• Publications: 1 publications found

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]

ENSG00000258667 (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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001530.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	NM_001530.4	MANE Select	c.774-3C>T		splice_region intron	N/A	NP_001521.1	D0VY79
	HIF1A	NM_001243084.2		c.846-3C>T		splice_region intron	N/A	NP_001230013.1	Q16665-3
	HIF1A	NM_181054.3		c.774-3C>T		splice_region intron	N/A	NP_851397.1	Q16665-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.774-3C>T		splice_region intron	N/A	ENSP00000338018.4	Q16665-1
	HIF1A	ENST00000539097.2	TSL:1	c.846-3C>T		splice_region intron	N/A	ENSP00000437955.1	Q16665-3
	HIF1A	ENST00000394997.5	TSL:1	c.777-3C>T		splice_region intron	N/A	ENSP00000378446.1	A8MYV6

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

African (AFR) AF: 0.000185 AC: 6 AN: 32498

American (AMR) AF: 0.000486 AC: 21 AN: 43190

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25710

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 83700

European-Finnish (FIN) AF: 0.00115 AC: 61 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00216 AC: 2338 AN: 1083986

Other (OTH) 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

African (AFR) AF: 0.000506 AC: 21 AN: 41494

American (AMR) AF: 0.00151 AC: 23 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00108

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		2.1
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

Other links and lift over

dbSNP: rs200037213; hg19: chr14-62199133;