chr14-61732540-G-T

Variant names:

• chr14-61732540-G-T
• rs191651195
• NM_001530.4:c.880+16G>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.880+16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,402,876 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: HIF1A NM_001530.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0280
• 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=-0.56).
• BP6: Variant 14-61732540-G-T is Benign according to our data. Variant chr14-61732540-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2920784.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 125 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.880+16G>T		intron	N/A	NP_001521.1	D0VY79
	HIF1A	NM_001243084.2		c.952+16G>T		intron	N/A	NP_001230013.1	Q16665-3
	HIF1A	NM_181054.3		c.880+16G>T		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.880+16G>T		intron	N/A	ENSP00000338018.4	Q16665-1
	HIF1A	ENST00000539097.2	TSL:1	c.952+16G>T		intron	N/A	ENSP00000437955.1	Q16665-3
	HIF1A	ENST00000394997.5	TSL:1	c.883+16G>T		intron	N/A	ENSP00000378446.1	A8MYV6

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000832 AC: 205 AN: 246248 AF XY: 0.000938

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000151

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.00132 AC: 1651 AN: 1250604 Hom.: 2 Cov.: 17 AF XY: 0.00129 AC XY: 817 AN XY: 632860

African (AFR) AF: 0.000136 AC: 4 AN: 29318

American (AMR) AF: 0.00127 AC: 56 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.000202 AC: 5 AN: 24810

East Asian (EAS) AF: 0.00 AC: 0 AN: 38656

South Asian (SAS) AF: 0.000135 AC: 11 AN: 81352

European-Finnish (FIN) AF: 0.000253 AC: 13 AN: 51362

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5398

European-Non Finnish (NFE) AF: 0.00163 AC: 1503 AN: 922334

Other (OTH) AF: 0.00109 AC: 58 AN: 53336

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74480

African (AFR) AF: 0.000337 AC: 14 AN: 41550

American (AMR) AF: 0.000654 AC: 10 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.000808

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	-0.56
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		-0.028
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs191651195; hg19: chr14-62199258;