rs568703831
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_153704.6(TMEM67):c.2661+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.0000705 in 1,447,134 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )
Consequence
TMEM67
NM_153704.6 splice_donor_region, intron
NM_153704.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9994
2
Clinical Significance
Conservation
PhyloP100: 5.64
Genes affected
TMEM67 (HGNC:28396): (transmembrane protein 67) The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]
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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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.2661+3A>G | splice_donor_region_variant, intron_variant | ENST00000453321.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.2661+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_153704.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000108 AC: 27AN: 249528Hom.: 0 AF XY: 0.000170 AC XY: 23AN XY: 135042
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GnomAD4 exome AF: 0.0000749 AC: 97AN: 1294896Hom.: 0 Cov.: 20 AF XY: 0.000115 AC XY: 75AN XY: 653052
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74424
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2022 | - - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | This sequence change falls in intron 25 of the TMEM67 gene. It does not directly change the encoded amino acid sequence of the TMEM67 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs568703831, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. ClinVar contains an entry for this variant (Variation ID: 262747). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2022 | In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge - |
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: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at