chr3-120647048-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_000187.4(HGD):c.474G>A(p.Pro158=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P158P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
HGD
NM_000187.4 synonymous
NM_000187.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.19
Genes affected
HGD (HGNC:4892): (homogentisate 1,2-dioxygenase) This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
Variant 3-120647048-C-T is Benign according to our data. Variant chr3-120647048-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 342748.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=-1.19 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| HGD | NM_000187.4 | c.474G>A | p.Pro158= | synonymous_variant | 8/14 | ENST00000283871.10 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HGD | ENST00000283871.10 | c.474G>A | p.Pro158= | synonymous_variant | 8/14 | 1 | NM_000187.4 | P1 | |
| HGD | ENST00000476082.2 | c.351G>A | p.Pro117= | synonymous_variant | 7/7 | 5 | |||
| HGD | ENST00000475447.2 | c.6G>A | p.Pro2= | synonymous_variant | 1/5 | 3 | |||
| HGD | ENST00000492108.5 | c.105G>A | p.Pro35= | synonymous_variant, NMD_transcript_variant | 3/6 | 2 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251042Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135652
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461266Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726962
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GnomAD4 genome 0.0000197 AC: 3AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74260
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Alkaptonuria Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 06, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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