14-61720494-G-C

Position:

• chr14-61720494-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PP5_Moderate BP4 BS2_Supporting

The NM_001530.4(HIF1A):​c.148G>C​(p.Val50Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00308 in 1,613,578 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: HIF1A NM_001530.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.80

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 14-61720494-G-C is Pathogenic according to our data. Variant chr14-61720494-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803796.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008302808). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 325 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/exons	MANE	UniProt
HIF1A	NM_001530.4	c.148G>C	p.Val50Leu	missense_variant	2/15	ENST00000337138.9
HIF1A-AS3	NR_144368.1	n.214-3477C>G		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.220G>C	p.Val74Leu	missense_variant	2/15
HIF1A	NM_181054.3	c.148G>C	p.Val50Leu	missense_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1A	ENST00000337138.9	c.148G>C	p.Val50Leu	missense_variant	2/15	1	NM_001530.4	P4
HIF1A-AS3	ENST00000660325.2	n.216-6492C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152198 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00196 AC: 491 AN: 250582 Hom.: 0 AF XY: 0.00201 AC XY: 272 AN XY: 135404

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00755

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00317 AC: 4639 AN: 1461262 Hom.: 14 Cov.: 30 AF XY: 0.00308 AC XY: 2238 AN XY: 726906

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00808

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.00359

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74488

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00298 Hom.: 1

Bravo AF: 0.00216

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maffucci syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0083	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.95	P;D;.;.
Vest4		0.62
MutPred		0.32		.;Gain of disorder (P = 0.1617);.;.;
MVP		0.49
MPC		0.97
ClinPred		0.035	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.47

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: rs61755705; hg19: chr14-62187212;