rs267607119

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_153704.6(TMEM67):c.2498T>C(p.Ile833Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,613,022 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.96

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 8-93808898-T-C is Pathogenic according to our data. Variant chr8-93808898-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93808898-T-C is described in Lovd as [Pathogenic]. Variant chr8-93808898-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.2498T>C	p.Ile833Thr	missense_variant	24/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.2498T>C	p.Ile833Thr	missense_variant	24/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251186

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1461088

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000832

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20232449, 19058225, 21633164, 25920555, 19574260, 23188109, 26092869, 19508969, 21866095, 28973083, 34426522, 28497568, 29974258, 35005812, 32359821) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2019	- -

Joubert syndrome 6

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Ile833Thr variant in TMEM67 was identified by our study in the compound heterozygous state, with a VUS, in one individual with Joubert syndrome. This variant has been reported pathogenic by OMIM in ClinVar (Variation ID: 1378) and has been identified in 0.007909% (10/126438) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267607119). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ile833Thr variant in TMEM67 has been reported in 10 individuals from a variety of ethnic backgrounds (Egypt, Croatia, Belgium, Japan, Germany) with Joubert syndrome and segregated with disease in 2 affected relatives from 1 family (PMID: 26092869, 19058225, 21633164, 19508969). The presence of this variant in combination with 4 variants (all reported pathogenic by the literature/OMIM in ClinVar and 1 reported pathogenic in ClinVar by additional submitters) and in 4 individuals with Joubert syndrome increases the likelihood that the p.Ile833Thr variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP1, PP3 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2011	- -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -

Meckel syndrome, type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

May 23, 2018

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 833 of the TMEM67 protein (p.Ile833Thr). This variant is present in population databases (rs267607119, gnomAD 0.008%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 19058225, 21866095, 26092869, 28497568, 28973083). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1378). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 25, 2021

- -

COACH syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2011

- -

Joubert syndrome and related disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 18, 2021

Variant summary: TMEM67 c.2498T>C (p.Ile833Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251186 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (4e-05 vs 0.0018), allowing no conclusion about variant significance. c.2498T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Joubert Syndrome And Related Disorders (example, Brancati_2009, Iannicelli_2010, Vilboux_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

TMEM67-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The c.2498T>C (p.Ile833Thr) variant has been previously reported as a compound heterozygous change in patients with TMEM67-related disorders (PMID: 19058225, 21866095, 21633164, 26092869, 28973083, 28497568, 29974258, 32359821, 34426522, 35005812). The c.2498T>C (p.Ile833Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/282526), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.2498T>C (p.Ile833Thr) is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.50

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.1

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.050

T;D

Polyphen

0.97

D;.

Vest4

0.96

MVP

1.0

MPC

0.63

ClinPred

0.76

GERP RS

5.7

Varity_R

0.37

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over