NM_153704.6:c.725A>G

Variant names:

Variant summary

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

The NM_153704.6(TMEM67):c.725A>G(p.Asn242Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,094 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.62

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, 0.857

PP5

Variant 8-93780603-A-G is Pathogenic according to our data. Variant chr8-93780603-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93780603-A-G is described in Lovd as [Likely_pathogenic]. Variant chr8-93780603-A-G is described in Lovd as [Likely_pathogenic]. Variant chr8-93780603-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.725A>G	p.Asn242Ser	missense_variant	Exon 8 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.725A>G	p.Asn242Ser	missense_variant	Exon 8 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251250

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

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

Jan 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26260382, 29302074, 25920555, 26092869, 30315573, 32000717, 33726816, 35032046, 28719906, 27491411) -

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 6

Pathogenic:3

Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A generation of sequencing tests were performed on the foetus's parents and the prior witness: the father carried c. 475 T >C;Het, mother carrying c. 725A> G;Het, daughter carrying c. 475 T >C; c. 725A> G double heterozygous, the fetus and the first witness inherited the genetic mutations of both parents -

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Asn242Ser variant in TMEM67 was identified by our study in one individual with Joubert syndrome. The p.Asn242Ser variant in TMEM67 was reported in 23 individuals (including 22 Iranians) with Joubert syndrome, segregated with disease in 22 affected relatives from 9 families (PMID: 28719906, 19574260), and has been identified in 0.002978% (1/33580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs775883520). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency and its prevalence in Iranian families with a shared haplotype suggests this is a founder variant (PMID: 28719906). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was also reported likely pathogenic in ClinVar prior to the publication of a paper about 22 Iranians from 9 families with this variant and Joubert syndrome (Variation ID: 216826). Two additional variants at the the same position, p.Asn242Thr and p.Asn242Lys, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23559409, 19574260). Position 242 in the TMEM67 protein has also been reported as a glycosylation site for GlcNAc, providing additional support that a change in this position may not be tolerated (Entry: Q5HYA8) In summary, this variant meets criteria to be classified as pathogenic for Joubert syndrome in an autosomal recessive manner based on the predicted impact of a change at position 242 in TMEM67 and cosegregation with Joubertssyndrome in multiple Iranian families. ACMG/AMP Criteria applied: PM2, PP3, PM5, PM1_Supporting, PP1_Strong (Richards 2015). -

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

Pathogenic:1

Jul 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869, 27491411, 28719906). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 216826). This variant is present in population databases (rs775883520, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 242 of the TMEM67 protein (p.Asn242Ser). -

Nephronophthisis 11

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PP3, PM5, PM1_Supporting, PP1_Strong -

Inborn genetic diseases

Pathogenic:1

Nov 28, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COACH syndrome 1

Pathogenic:1

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000216826). Different missense changes at the same codon (p.Asn242Lys, p.Asn242Thr) have been reported to be associated with TMEM67 -related disorder (PMID: 19574260 , 23559409). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

.;M;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.91, 0.90

MutPred

0.61

.;Loss of stability (P = 0.0382);.;

MVP

1.0

MPC

0.40

ClinPred

0.99

GERP RS

5.8

Varity_R

0.33

gMVP

0.90

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