14-61734128-T-TC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001530.4(HIF1A):c.881-4dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,512,762 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (11 hom.)
• Consequence: HIF1A NM_001530.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

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 -10 ACMG points.

• BP6: Variant 14-61734128-T-TC is Benign according to our data. Variant chr14-61734128-T-TC is described in ClinVar as [Benign]. Clinvar id is 727387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00596 (907/152220) while in subpopulation AFR AF= 0.0204 (847/41518). AF 95% confidence interval is 0.0193. There are 13 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 885 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIF1A	NM_001530.4	c.881-4dup		splice_polypyrimidine_tract_variant, intron_variant		ENST00000337138.9
HIF1A-AS3	NR_144368.1	n.213+16756_213+16757insG		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.953-4dup		splice_polypyrimidine_tract_variant, intron_variant
HIF1A	NM_181054.3	c.881-4dup		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1A	ENST00000337138.9	c.881-4dup		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001530.4	P4
HIF1A-AS3	ENST00000660325.2	n.215+16756_215+16757insG		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 885 AN: 152102 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00154 AC: 301 AN: 195662 Hom.: 4 AF XY: 0.00105 AC XY: 113 AN XY: 107264

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.00149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000466

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000928

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000621 AC: 845 AN: 1360542 Hom.: 11 Cov.: 27 AF XY: 0.000571 AC XY: 383 AN XY: 670986

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000279

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.00596 AC: 907 AN: 152220 Hom.: 13 Cov.: 32 AF XY: 0.00601 AC XY: 447 AN XY: 74428

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00347 Hom.: 0

Bravo AF: 0.00721

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

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs112401635; hg19: chr14-62200846;