rs772437766
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_153704.6(TMEM67):c.245C>G(p.Pro82Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000783 in 1,277,496 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P82S) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 7.8e-7 ( 0 hom. )
Consequence
TMEM67
NM_153704.6 missense
NM_153704.6 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 3.24
Publications
5 publications found
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]
TMEM67 Gene-Disease associations (from GenCC):
- ciliopathyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
- COACH syndrome 1Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
- Meckel syndrome, type 3Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
- nephronophthisis 11Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- COACH syndrome 1Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
- Joubert syndrome 6Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Joubert syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Meckel syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Senior-Boichis syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_153704.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-93755798-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217715.
PP5
Variant 8-93755799-C-G is Pathogenic according to our data. Variant chr8-93755799-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217714.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_153704.6. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TMEM67 | TSL:1 MANE Select | c.245C>G | p.Pro82Arg | missense | Exon 2 of 28 | ENSP00000389998.3 | Q5HYA8 | ||
| TMEM67 | TSL:1 | c.245C>G | p.Pro82Arg | missense | Exon 2 of 27 | ENSP00000388671.2 | C9JRQ8 | ||
| TMEM67 | TSL:1 | n.265C>G | non_coding_transcript_exon | Exon 2 of 17 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 7.83e-7 AC: 1AN: 1277496Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 640562 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1277496
Hom.:
Cov.:
26
AF XY:
AC XY:
0
AN XY:
640562
show subpopulations
African (AFR)
AF:
AC:
0
AN:
28624
American (AMR)
AF:
AC:
0
AN:
40592
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23656
East Asian (EAS)
AF:
AC:
0
AN:
36846
South Asian (SAS)
AF:
AC:
0
AN:
75874
European-Finnish (FIN)
AF:
AC:
0
AN:
51216
Middle Eastern (MID)
AF:
AC:
0
AN:
4648
European-Non Finnish (NFE)
AF:
AC:
1
AN:
963028
Other (OTH)
AF:
AC:
0
AN:
53012
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
30
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
Pathogenic
VUS
Benign
Condition
1
1
-
Joubert syndrome 6 (2)
1
-
-
Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of solvent accessibility (P = 0.1045)
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
Splicevardb
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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