rs17099141

Variant names:

• chr14-61727521-G-A
• rs17099141
• NM_001530.4:c.639G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_001530.4(HIF1A):​c.639G>A​(p.Lys213Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,613,694 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (97 hom., cov: 32)
  • Exomes 𝑓: 0.021 (410 hom.)
• Consequence: HIF1A NM_001530.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.35
• Publications: 14 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:):

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 14-61727521-G-A is Benign according to our data. Variant chr14-61727521-G-A is described in ClinVar as [Benign]. Clinvar id is 2920757.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.639G>A	p.Lys213Lys	synonymous_variant	Exon 6 of 15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.711G>A	p.Lys237Lys	synonymous_variant	Exon 6 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.639G>A	p.Lys213Lys	synonymous_variant	Exon 6 of 14		NP_851397.1
HIF1A-AS3	NR_144368.1	n.214-10504C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.639G>A	p.Lys213Lys	synonymous_variant	Exon 6 of 15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4346 AN: 151954 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0176 AC: 4414 AN: 251410 AF XY: 0.0167

Gnomad AFR exome AF: 0.0603

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0206 AC: 30135 AN: 1461622 Hom.: 410 Cov.: 31 AF XY: 0.0200 AC XY: 14514 AN XY: 727146

African (AFR) AF: 0.0603 AC: 2018 AN: 33468

American (AMR) AF: 0.0107 AC: 477 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00815 AC: 213 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00565 AC: 487 AN: 86256

European-Finnish (FIN) AF: 0.0179 AC: 956 AN: 53416

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5768

European-Non Finnish (NFE) AF: 0.0222 AC: 24692 AN: 1111798

Other (OTH) AF: 0.0206 AC: 1246 AN: 60386

GnomAD4 genome AF: 0.0287 AC: 4361 AN: 152072 Hom.: 97 Cov.: 32 AF XY: 0.0277 AC XY: 2060 AN XY: 74334

African (AFR) AF: 0.0589 AC: 2442 AN: 41438

American (AMR) AF: 0.0140 AC: 214 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4822

European-Finnish (FIN) AF: 0.0178 AC: 188 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0207 AC: 1410 AN: 67998

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0240 Hom.: 51

Bravo AF: 0.0303

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0176

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 04, 2024

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
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs17099141; hg19: chr14-62194239; COSMIC: COSV60188266;