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rs587777284

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate

The NM_012338.4(TSPAN12):c.67-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TSPAN12
NM_012338.4 splice_acceptor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.09
Variant links:
Genes affected
TSPAN12 (HGNC:21641): (tetraspanin 12) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.4, offset of 14, new splice context is: ccccacttaatgtccatcAGtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
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.
PP5
Variant 7-120840110-C-G is Pathogenic according to our data. Variant chr7-120840110-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 126504.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-120840110-C-G is described in Lovd as [Likely_pathogenic]. Variant chr7-120840110-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSPAN12NM_012338.4 linkuse as main transcriptc.67-1G>C splice_acceptor_variant ENST00000222747.8
TSPAN12XM_005250239.4 linkuse as main transcriptc.67-1G>C splice_acceptor_variant
TSPAN12XM_047420095.1 linkuse as main transcriptc.67-1G>C splice_acceptor_variant
TSPAN12XM_047420096.1 linkuse as main transcriptc.67-1G>C splice_acceptor_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSPAN12ENST00000222747.8 linkuse as main transcriptc.67-1G>C splice_acceptor_variant 1 NM_012338.4 P1O95859-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Exudative vitreoretinopathy 5 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 14, 2012- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJul 06, 2023For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 3 and introduces a premature termination codon (PMID: 22427576). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 126504). Disruption of this splice site has been observed in individuals with exudative vitreoretinopathy (PMID: 22427576; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the TSPAN12 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.17
Cadd
Pathogenic
30
Dann
Uncertain
0.99
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.97
D
MutationTaster
Benign
1.0
D;D
GERP RS
4.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.95
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777284; hg19: chr7-120480164; API