rs34005929

chr14-61740835-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001530.4(HIF1A):c.1740G>A(p.Leu580=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,614,068 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: HIF1A NM_001530.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.117

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 14-61740835-G-A is Benign according to our data. Variant chr14-61740835-G-A is described in ClinVar as [Benign]. Clinvar id is 716776.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.117 with no splicing effect.
• BS2: High AC in GnomAd at 305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIF1A	NM_001530.4	c.1740G>A	p.Leu580=	synonymous_variant	12/15	ENST00000337138.9
HIF1A-AS3	NR_144368.1	n.213+10050C>T		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.1812G>A	p.Leu604=	synonymous_variant	12/15
HIF1A	NM_181054.3	c.1740G>A	p.Leu580=	synonymous_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1A	ENST00000337138.9	c.1740G>A	p.Leu580=	synonymous_variant	12/15	1	NM_001530.4	P4
HIF1A-AS3	ENST00000660325.2	n.215+10050C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00241 AC: 607 AN: 251472 Hom.: 1 AF XY: 0.00249 AC XY: 338 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00279 AC: 4084 AN: 1461820 Hom.: 11 Cov.: 31 AF XY: 0.00286 AC XY: 2080 AN XY: 727220

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74448

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00265 Hom.: 0

Bravo AF: 0.00175

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00279

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.9
Dann	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs34005929; hg19: chr14-62207553;