chr19-35546524-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_032635.4(TMEM147):c.148-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000124 in 1,611,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_032635.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM147 | NM_032635.4 | c.148-2A>G | splice_acceptor_variant, intron_variant | Intron 2 of 6 | ENST00000222284.10 | NP_116024.1 | ||
TMEM147 | NM_001242597.2 | c.1-2A>G | splice_acceptor_variant, intron_variant | Intron 1 of 5 | NP_001229526.1 | |||
TMEM147 | NM_001242598.2 | c.148-2A>G | splice_acceptor_variant, intron_variant | Intron 2 of 4 | NP_001229527.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459754Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726092
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74308
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2023 | The c.148-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 3 of the TMEM147 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. Based on data from gnomAD, the G allele has an overall frequency of 0.001% (1/152142) total alleles studied. The highest observed frequency was 0.002% (1/41422) of African/African American alleles. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at