Genetic Variant HIF1A:n.221dupT (chr14-61697832-A-AT) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The ENST00000557538.5(HIF1A):n.221dupT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,379,122 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 1 hom. )

Consequence

HIF1A
ENST00000557538.5 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.274

Publications

0 publications found

Variant links:

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 links:

HIF1A-AS3 (HGNC:):

HIF1A-AS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS2

High AC in GnomAd4 at 71 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	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4 link	c.35+2003dupT	intron_variant	Intron 1 of 14	ENST00000337138.9	NP_001521.1	Q16665-1D0VY79
HIF1A	NM_001243084.2 link	c.-9dupT	5_prime_UTR_variant	Exon 1 of 15		NP_001230013.1	Q16665-3
HIF1A	NM_181054.3 link	c.35+2003dupT	intron_variant	Intron 1 of 13		NP_851397.1	Q16665-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9 link	c.35+2003dupT		intron_variant	Intron 1 of 14	1	NM_001530.4	ENSP00000338018.4		Q16665-1

Frequencies

GnomAD3 genomes

AF:

0.000478

AC:

AN:

150588

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000531

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000282

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.0223

AC:

1007

AN:

45182

AF XY:

0.0221

show subpopulations

Gnomad AFR exome

AF:

0.0210

Gnomad AMR exome

AF:

0.0276

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0253

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0297

GnomAD4 exome

AF:

0.00327

AC:

4019

AN:

1228418

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

2074

AN XY:

603886

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00334

AC:

AN:

26648

American (AMR)

AF:

0.0105

AC:

232

AN:

22024

Ashkenazi Jewish (ASJ)

AF:

0.00611

AC:

126

AN:

20628

East Asian (EAS)

AF:

0.00848

AC:

263

AN:

31016

South Asian (SAS)

AF:

0.00712

AC:

450

AN:

63176

European-Finnish (FIN)

AF:

0.00324

AC:

AN:

28682

Middle Eastern (MID)

AF:

0.00772

AC:

AN:

5052

European-Non Finnish (NFE)

AF:

0.00258

AC:

2534

AN:

980278

Other (OTH)

AF:

0.00379

AC:

193

AN:

50914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.274

Heterozygous variant carriers

567

1135

1702

2270

2837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000471

AC:

AN:

150704

Hom.:

Cov.:

AF XY:

0.000543

AC XY:

AN XY:

73624

show subpopulations

African (AFR)

AF:

0.000364

AC:

AN:

41180

American (AMR)

AF:

0.000530

AC:

AN:

15088

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

3448

East Asian (EAS)

AF:

0.00271

AC:

AN:

5170

South Asian (SAS)

AF:

0.00147

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000282

AC:

AN:

67470

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0108

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.27

Mutation Taster

=298/2

polymorphism

(source)

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

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14-61697832-ATTT-ATTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over