rs780823805
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_153704.6(TMEM67):c.224G>A(p.Gly75Glu) variant causes a missense, splice region change. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G75R) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 26)
Exomes 𝑓: 0.0000073 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TMEM67
NM_153704.6 missense, splice_region
NM_153704.6 missense, splice_region
Scores
7
6
6
Splicing: ADA: 0.9988
2
Clinical Significance
Conservation
PhyloP100: 4.51
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.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_153704.6
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM67 | NM_153704.6 | c.224G>A | p.Gly75Glu | missense_variant, splice_region_variant | 2/28 | ENST00000453321.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM67 | ENST00000453321.8 | c.224G>A | p.Gly75Glu | missense_variant, splice_region_variant | 2/28 | 1 | NM_153704.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 123324Hom.: 0 Cov.: 26 FAILED QC
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GnomAD3 exomes AF: 0.0000358 AC: 6AN: 167466Hom.: 0 AF XY: 0.0000216 AC XY: 2AN XY: 92484
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GnomAD4 exome AF: 0.00000734 AC: 5AN: 681202Hom.: 0 Cov.: 14 AF XY: 0.00000562 AC XY: 2AN XY: 356174
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 123324Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 58242
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
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 | Invitae | Jan 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 75 of the TMEM67 protein (p.Gly75Glu). This variant is present in population databases (rs780823805, gnomAD 0.06%). 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: 411582). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2022 | The c.224G>A (p.G75E) alteration is located in exon 2 (coding exon 2) of the TMEM67 gene. This alteration results from a G to A substitution at nucleotide position 224, causing the glycine (G) at amino acid position 75 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 | Nov 16, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Benign
T;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at