chr8-93765573-CAG-C

Position:

• chr8-93765573-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153704.6(TMEM67):​c.579_580delAG​(p.Gly195fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000145 in 1,611,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TMEM67 NM_153704.6 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.13

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-93765573-CAG-C is Pathogenic according to our data. Variant chr8-93765573-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93765573-CAG-C is described in Lovd as [Pathogenic]. Variant chr8-93765573-CAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.579_580delAG	p.Gly195fs	frameshift_variant, splice_region_variant	6/28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.579_580delAG	p.Gly195fs	frameshift_variant, splice_region_variant	6/28	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151992 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251350 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135868

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1459010 Hom.: 0 AF XY: 0.000138 AC XY: 100 AN XY: 726080

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151992 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74242

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel syndrome, type 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2022	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2023	Observed in the homozygous state or with another variant in the TMEM67 gene in multiple patients with Joubert syndrome and related disorders in published literature (Brancati et al., 2009; Iannicelli et al., 2010; Watson et al., 2016; Summers et al., 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20232449, 29146704, 31974414, 28431631, 19058225, 28497568, 12368986, 26729329, 30712878, 26092869, 23559409, 31980526, 33432080, 31589614) -

Joubert syndrome 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 18, 2014	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change creates a premature translational stop signal (p.Gly195Ilefs*13) in the TMEM67 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs386834202, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome, COACH syndrome or Meckel-Gruber syndrome (PMID: 19058225, 20232449, 23559409, 26092869, 26729329, 28431631). ClinVar contains an entry for this variant (Variation ID: 56783). 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

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PVS1+PM2_Supporting+PM3 -

Joubert syndrome and related disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 30, 2023

Variant summary: TMEM67 c.579_580delAG (p.Gly195IlefsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00019 in 251350 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders (0.00019 vs 0.0018), allowing no conclusion about variant significance. c.579_580delAG has been reported in the literature in individuals affected with Joubert Syndrome including compound heterozygote genotypes (e.g. Fleming_2017) and in a homozygous fetus from a Meckel syndrome family (e.g. Iannicelli_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20232449, 29146704). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

TMEM67-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The TMEM67 c.579_580delAG (p.Gly195IlefsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly195IlefsTer13 variant has been reported in five studies in which it is found in a total of seven individuals, including one homozygote and one compound heterozygote with Meckel syndrome, one homozygote with either Meckel or Joubert syndrome, two compound heterozygotes with Joubert syndrome, and two compound heterozygotes with COACH syndrome (Brancati et al. 2009; Iannicelli et al. 2010; Halbritter et al. 2013; Bachmann-Gagescu et al. 2015; Watson et al. 2016). Control data are unavailable for the p.Gly195IlefsTer13 variant, which is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and due to the potential impact of frameshift variants, the p.Gly195IlefsTer13 variant is classified as pathogenic for TMEM67-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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

Other links and lift over

dbSNP: rs386834202; hg19: chr8-94777801;