rs747025617

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_153704.6(TMEM67):c.1645C>T(p.Arg549Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.91

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 8-93793267-C-T is Pathogenic according to our data. Variant chr8-93793267-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 530903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.1645C>T	p.Arg549Cys	missense_variant	Exon 16 of 28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.1645C>T	p.Arg549Cys	missense_variant	Exon 16 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251456

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000437

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 10, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 549 of the TMEM67 protein (p.Arg549Cys). This variant is present in population databases (rs747025617, gnomAD 0.02%). This missense change has been observed in individuals with Meckel syndrome (PMID: 21493627, 23351400). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 530903). 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%. Experimental studies have shown that this missense change affects TMEM67 function (PMID: 26035863). For these reasons, this variant has been classified as Pathogenic. -

Meckel syndrome, type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant p.R549C in TMEM67 (NM_153704.6) has been previously reported as homozygous or in combination with another TMEM67 variant in individuals affected with Meckel syndrome ( Hopp et al, 2011). The p.R549C variant is observed in 4/18,394 (0.0217%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Experimental studies have shown that this missense change is unable to rescue de-regulated Wnt/beta-catenin signaling that is present in a null knockout mouse model (Abdelhamed et al, 2015). There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R549C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1645 in TMEM67 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. No significant variants in gene TMEM67 were detected in the spouse. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 27, 2023

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2022

Published functional studies demonstrated that mouse embryonic fibroblasts homozygous for the R549C variant failed to rescue basal responses to Wnt3a (Abdelhamed et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24039893, 21493627, 26035863, 26191240, 23351400, 29304564) -

Joubert syndrome and related disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 27, 2021

Variant summary: TMEM67 c.1645C>T (p.Arg549Cys) 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 5.6e-05 in 251456 control chromosomes (gnomAD). This frequency is lower than the maximum expected for a pathogenic variant in TMEM67 causing Joubert Syndrome and Related Disorders (5.6e-05 vs 0.0018), allowing no conclusion about variant significance. c.1645C>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Joubert Syndrome and Related Disorders (Hopp_2011, Szymanska_2012, Zhang_2015), including segregation evidence in one of the reported families (Zhang_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant failed to restore the de-regulated Wnt/beta-catenin signaling in Tmem67 -/- mouse embryonic fibroblasts (Abdelhamed_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.90

MVP

1.0

MPC

0.66

ClinPred

0.80

GERP RS

5.7

Varity_R

0.82

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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