1-179914059-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_015602.4(TOR1AIP1):c.964+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000112 in 1,612,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
TOR1AIP1
NM_015602.4 splice_donor_5th_base, intron
NM_015602.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.24
Genes affected
TOR1AIP1 (HGNC:29456): (torsin 1A interacting protein 1) This gene encodes a type 2 integral membrane protein that binds A- and B-type lamins. The encoded protein localizes to the inner nuclear membrane and may be involved in maintaining the attachment of the nuclear membrane to the nuclear lamina during cell division. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000919 (14/152302) while in subpopulation SAS AF= 0.00269 (13/4830). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TOR1AIP1 | NM_015602.4 | c.964+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000606911.7 | NP_056417.2 | |||
| TOR1AIP1 | NM_001267578.2 | c.967+5G>A | splice_donor_5th_base_variant, intron_variant | NP_001254507.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TOR1AIP1 | ENST00000606911.7 | c.964+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_015602.4 | ENSP00000476687 | P4 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000216 AC: 54AN: 249850Hom.: 0 AF XY: 0.000289 AC XY: 39AN XY: 135048
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GnomAD4 exome AF: 0.000114 AC: 166AN: 1459888Hom.: 1 Cov.: 30 AF XY: 0.000162 AC XY: 118AN XY: 726210
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GnomAD4 genome 0.0000919 AC: 14AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74466
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2Y Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 06, 2022 | This sequence change falls in intron 9 of the TOR1AIP1 gene. It does not directly change the encoded amino acid sequence of the TOR1AIP1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs561816881, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TOR1AIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576365). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at