chr5-78181507-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2
The NM_003664.5(AP3B1):c.942G>A(p.Ala314=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,612,038 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003664.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP3B1 | NM_003664.5 | c.942G>A | p.Ala314= | splice_region_variant, synonymous_variant | 8/27 | ENST00000255194.11 | |
AP3B1 | NM_001271769.2 | c.795G>A | p.Ala265= | splice_region_variant, synonymous_variant | 8/27 | ||
AP3B1 | NM_001410752.1 | c.942G>A | p.Ala314= | splice_region_variant, synonymous_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP3B1 | ENST00000255194.11 | c.942G>A | p.Ala314= | splice_region_variant, synonymous_variant | 8/27 | 1 | NM_003664.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00110 AC: 167AN: 152070Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00189 AC: 472AN: 250310Hom.: 1 AF XY: 0.00154 AC XY: 209AN XY: 135318
GnomAD4 exome AF: 0.000603 AC: 881AN: 1459850Hom.: 6 Cov.: 31 AF XY: 0.000587 AC XY: 426AN XY: 726294
GnomAD4 genome ? AF: 0.00108 AC: 165AN: 152188Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95AN XY: 74390
ClinVar
Submissions by phenotype
Hermansky-Pudlak syndrome 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 20, 2023 | Variant summary: AP3B1 c.942G>A (p.Ala314Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the 5' canonical splicing donor site. One predict the variant weakens the 5' canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0019 in 250310 control chromosomes, predominantly at a frequency of 0.0097 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.942G>A in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at