14-61740835-G-A

Variant names:

• chr14-61740835-G-A
• rs34005929
• NM_001530.4:c.1740G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BP6_Moderate BP7 BS2_Supporting

The NM_001530.4(HIF1A):​c.1740G>A​(p.Leu580Leu) 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
• Publications: 10 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 -8 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 GnomAd4 at 306 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.1740G>A	p.Leu580Leu	synonymous_variant	Exon 12 of 15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.1812G>A	p.Leu604Leu	synonymous_variant	Exon 12 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.1740G>A	p.Leu580Leu	synonymous_variant	Exon 12 of 14		NP_851397.1
HIF1A-AS3	NR_144368.1	n.213+10050C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.1740G>A	p.Leu580Leu	synonymous_variant	Exon 12 of 15	1	NM_001530.4	ENSP00000338018.4

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

GnomAD2 exomes AF: 0.00241 AC: 607 AN: 251472 AF XY: 0.00249

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00319 AC: 275 AN: 86258

European-Finnish (FIN) AF: 0.00253 AC: 135 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00314 AC: 3490 AN: 1111944

Other (OTH) AF: 0.00230 AC: 139 AN: 60396

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

African (AFR) AF: 0.000313 AC: 13 AN: 41552

American (AMR) AF: 0.00144 AC: 22 AN: 15282

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

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

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.000944 AC: 10 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00354 AC: 241 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

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

Jul 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.56
CADD	Benign	6.9
DANN	Benign	0.84
PhyloP100		-0.12
Mutation Taster		=100/0	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: rs34005929; hg19: chr14-62207553; COSMIC: COSV108114184;