14-61697832-AT-A

Variant names:

• chr14-61697832-AT-A
• rs113243889
• ENST00000557538.5:n.221delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001530.4(HIF1A):​c.35+2003delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,402,824 control chromosomes in the GnomAD database, including 174 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (97 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (77 hom.)
• Consequence: HIF1A NM_001530.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.274
• Publications: 0 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]

HIF1A-AS3 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 14-61697832-AT-A is Benign according to our data. Variant chr14-61697832-AT-A is described in ClinVar as [Benign]. Clinvar id is 2920767.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.35+2003delT		intron_variant	Intron 1 of 14	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.-9delT		5_prime_UTR_variant	Exon 1 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.35+2003delT		intron_variant	Intron 1 of 13		NP_851397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.35+2003delT		intron_variant	Intron 1 of 14	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2804 AN: 150592 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00810

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000296

Gnomad OTH AF: 0.0189

GnomAD2 exomes AF: 0.0156 AC: 706 AN: 45182 AF XY: 0.0131

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.00524

Gnomad EAS exome AF: 0.0201

Gnomad FIN exome AF: 0.00562

Gnomad NFE exome AF: 0.00665

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.00276 AC: 3451 AN: 1252116 Hom.: 77 Cov.: 29 AF XY: 0.00260 AC XY: 1600 AN XY: 615848

African (AFR) AF: 0.0711 AC: 1929 AN: 27126

American (AMR) AF: 0.00788 AC: 177 AN: 22466

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 26 AN: 21024

East Asian (EAS) AF: 0.00552 AC: 175 AN: 31722

South Asian (SAS) AF: 0.00208 AC: 135 AN: 64880

European-Finnish (FIN) AF: 0.00167 AC: 49 AN: 29372

Middle Eastern (MID) AF: 0.00410 AC: 21 AN: 5126

European-Non Finnish (NFE) AF: 0.000565 AC: 564 AN: 998504

Other (OTH) AF: 0.00723 AC: 375 AN: 51896

GnomAD4 genome AF: 0.0188 AC: 2832 AN: 150708 Hom.: 97 Cov.: 32 AF XY: 0.0187 AC XY: 1380 AN XY: 73624

African (AFR) AF: 0.0632 AC: 2604 AN: 41180

American (AMR) AF: 0.00809 AC: 122 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5170

South Asian (SAS) AF: 0.000630 AC: 3 AN: 4762

European-Finnish (FIN) AF: 0.00117 AC: 12 AN: 10300

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000296 AC: 20 AN: 67474

Other (OTH) AF: 0.0187 AC: 39 AN: 2086

Alfa AF: 0.00558 Hom.: 0

Bravo AF: 0.0215

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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
PhyloP100		0.27
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113243889; hg19: chr14-62164550; COSMIC: COSV104397768; COSMIC: COSV104397768;