chr19-46305359-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_152795.4(HIF3A):āc.332A>Gā(p.Glu111Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000016 ( 0 hom. )
Consequence
HIF3A
NM_152795.4 missense
NM_152795.4 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
HIF3A (HGNC:15825): (hypoxia inducible factor 3 subunit alpha) The protein encoded by this gene is the alpha-3 subunit of one of several alpha/beta-subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia). The alpha-3 subunit lacks the transactivation domain found in factors containing either the alpha-1 or alpha-2 subunits. It is thought that factors containing the alpha-3 subunit are negative regulators of hypoxia-inducible gene expression. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HIF3A | NM_152795.4 | c.332A>G | p.Glu111Gly | missense_variant | 3/15 | ENST00000377670.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HIF3A | ENST00000377670.9 | c.332A>G | p.Glu111Gly | missense_variant | 3/15 | 1 | NM_152795.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152108Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250950Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135692
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727174
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2023 | The c.332A>G (p.E111G) alteration is located in exon 3 (coding exon 3) of the HIF3A gene. This alteration results from a A to G substitution at nucleotide position 332, causing the glutamic acid (E) at amino acid position 111 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;T;D
Polyphen
D;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at