rs772449181
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_153704.6(TMEM67):c.2556+4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,565,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000028 ( 1 hom. )
Consequence
TMEM67
NM_153704.6 splice_region, intron
NM_153704.6 splice_region, intron
Scores
2
Splicing: ADA: 0.001153
2
Clinical Significance
Conservation
PhyloP100: 0.522
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 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TMEM67 | NM_153704.6 | c.2556+4T>G | splice_region_variant, intron_variant | ENST00000453321.8 | NP_714915.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TMEM67 | ENST00000453321.8 | c.2556+4T>G | splice_region_variant, intron_variant | 1 | NM_153704.6 | ENSP00000389998.3 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250888Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135624
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GnomAD4 exome AF: 0.0000283 AC: 40AN: 1413722Hom.: 1 Cov.: 24 AF XY: 0.0000326 AC XY: 23AN XY: 706276
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GnomAD4 genome 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74282
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2022 | This sequence change falls in intron 24 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 (rs772449181, gnomAD 0.02%). 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: 363924). 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 is not likely to affect RNA splicing. 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. - |
Meckel syndrome, type 3 Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2024 | - - |
Nephronophthisis 11 Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 08, 2024 | - - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 14, 2022 | - - |
Joubert syndrome 6 Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
TMEM67-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2024 | The TMEM67 c.2556+4T>G variant is predicted to interfere with splicing. This variant is predicted to modestly impact splicing, however such predictions are not equivalent to functional evidence (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at