14-61727650-T-C

Variant names:

• chr14-61727650-T-C
• rs113805602
• NM_001530.4:c.768T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001530.4(HIF1A):​c.768T>C​(p.Asp256Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,604,242 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: HIF1A NM_001530.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84
• 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]

HIF1A-AS3 (HGNC:):

HIF1A-AS3 (HGNC:54284): (HIF1A antisense RNA 3)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 14-61727650-T-C is Benign according to our data. Variant chr14-61727650-T-C is described in ClinVar as [Benign]. Clinvar id is 727386.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.84 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00602 (917/152276) while in subpopulation AFR AF = 0.0206 (856/41558). AF 95% confidence interval is 0.0195. There are 13 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 917 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HIF1A	NM_001530.4	c.768T>C	p.Asp256Asp	synonymous_variant	Exon 6 of 15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2	c.840T>C	p.Asp280Asp	synonymous_variant	Exon 6 of 15		NP_001230013.1
HIF1A	NM_181054.3	c.768T>C	p.Asp256Asp	synonymous_variant	Exon 6 of 14		NP_851397.1
HIF1A-AS3	NR_144368.1	n.214-10633A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9	c.768T>C	p.Asp256Asp	synonymous_variant	Exon 6 of 15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 895 AN: 152156 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0201

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: 0.00287

GnomAD2 exomes AF: 0.00151 AC: 380 AN: 251056 AF XY: 0.00111

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000685 AC: 995 AN: 1451966 Hom.: 11 Cov.: 28 AF XY: 0.000624 AC XY: 451 AN XY: 723148

African (AFR) AF: 0.0213 AC: 707 AN: 33228

American (AMR) AF: 0.00154 AC: 69 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5742

European-Non Finnish (NFE) AF: 0.0000816 AC: 90 AN: 1103092

Other (OTH) AF: 0.00193 AC: 116 AN: 60066

GnomAD4 genome AF: 0.00602 AC: 917 AN: 152276 Hom.: 13 Cov.: 32 AF XY: 0.00606 AC XY: 451 AN XY: 74470

African (AFR) AF: 0.0206 AC: 856 AN: 41558

American (AMR) AF: 0.00314 AC: 48 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00735

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 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	-0.61
CADD	Benign	6.3
DANN	Benign	0.77
PhyloP100		1.8
Mutation Taster		=97/3	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: rs113805602; hg19: chr14-62194368;