ENST00000621467.5:c.-378C>T

Variant names:

• chr2-201640915-G-A
• rs199469707
• ENST00000621467.5:c.-378C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000621467.5(TMEM237):​c.-378C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000718 in 1,602,646 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: TMEM237 ENST00000621467.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.80

Genes affected

TMEM237 (HGNC:14432): (transmembrane protein 237) The protein encoded by this gene is a tetraspanin protein that is thought to be involved in WNT signaling. Defects in this gene are a cause of Joubert syndrome-14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.475
• PP5: Variant 2-201640915-G-A is Pathogenic according to our data. Variant chr2-201640915-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201640915-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM237	NM_001044385.3	c.52C>T	p.Arg18*	stop_gained	Exon 2 of 13	ENST00000409883.7	NP_001037850.1
TMEM237	NM_152388.4	c.28C>T	p.Arg10*	stop_gained	Exon 2 of 13		NP_689601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7	c.52C>T	p.Arg18*	stop_gained	Exon 2 of 13	5	NM_001044385.3	ENSP00000386264.2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152010 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000607 AC: 15 AN: 247028 Hom.: 0 AF XY: 0.0000448 AC XY: 6 AN XY: 133946

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: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000731 AC: 106 AN: 1450636 Hom.: 0 Cov.: 30 AF XY: 0.0000763 AC XY: 55 AN XY: 720708

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000915

Gnomad4 OTH exome AF: 0.0000668

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152010 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74232

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000926 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000368 AC: 3

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 14 Pathogenic:7

Oct 05, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 22, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature termination codon at position 18 in exon 2 (of 13) of TMEM237 ,p.(Arg18*). It is expected to result in an absent or disrupted protein product, and loss of function is the established mechanism of disease for this gene (PMID: 22152675). The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with a recessive condition (rs199469707, 16/278,360 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in individuals with Joubert syndrome, and segregates with the condition in the homozygous state in multiple related Canadian Hutterite families. Fibroblast cell lines from homozygous cases show loss of TMEM237 expression, and defective ciliogenesis and pairing of centrioles (PMID: 22152675). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2_Supporting, PP4. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 14 (MIM#614424). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as homozygous in many related Hutterite individuals with severe Joubert syndrome related disorder (PMIDs: 17603801, 22152675). It has been described as a founder variant in Hutterite individuals (PMID: 31710777). It has also been reported as pathogenic in ClinVar, however ethnicity of those individuals were not provided. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using patient fibroblast line showed defective ciliogenesis and pairing of centrioles, and reduced TMEM237 expression level (PMID: 22152675). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 04, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 2 of 13 is predicted to result in loss of normal protein function. This variant has been previously reported as a homozygous change in ten Canadian Hutterite patients with intellectual disability, a characteristic facial appearance, encephalocele, coloboma, renal disease, and additional features consistent with a diagnosis of a Joubert syndrome related disorder (PMID: 22152675, 17603801). The variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/275258) and thus is presumed to be rare. Based on the available evidence, c.52C>T (p.Arg18Ter) variant is classified as pathogenic. -

Dec 29, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg18*) in the TMEM237 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM237 are known to be pathogenic (PMID: 22152675). This variant is present in population databases (rs199469707, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Joubert syndrome (PMID: 22152675, 22981120). It is commonly reported in individuals of Hutterite ancestry (PMID: 22152675, 22981120). ClinVar contains an entry for this variant (Variation ID: 31180). For these reasons, this variant has been classified as Pathogenic. -

Dec 21, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 31964843, 36788019, 22981120, 27247959, 25697177, 22152675, 31019026) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

TMEM237-related disorder Pathogenic:1

Mar 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TMEM237 c.52C>T variant is predicted to result in premature protein termination (p.Arg18*). This variant is documented as causative for Joubert syndrome (Huang et al. 2011. PubMed ID: 22152675). Approximately 6% of Canadian Hutterites are carriers for this pathogenic variant (Huang et al. 2011. PubMed ID: 22152675). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in TMEM237 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Joubert syndrome and related disorders Pathogenic:1

May 06, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMEM237 c.52C>T (p.Arg18X) 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. Truncations downstream of this position have been classified as pathogenic within ClinVar. The variant allele was found at a frequency of 6.1e-05 in 247028 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TMEM237 causing Joubert Syndrome And Related Disorders (6.1e-05 vs 0.0004), allowing no conclusion about variant significance. The variant was found at an 8% carrier frequency rate within the Hutterite communities of Canada and the Northern United States, indicating a founder effect for the variant. Subsequently, c.52C>T has been reported in the literature in multiple homozygous individuals affected with Joubert Syndrome And Related Disorders from Hutterite communities (Huang_2011). The variant was also found in at least one compound heterozygous, presumably non-Hutterite individual (Clark_2019). These data indicate that the variant is very likely to be associated with disease. Huang_2011 has shown that fibroblasts homozygous for the variant have defects in ciliogenesis with no detectable ciliated cells as seen via microscopy. Huang_2011 also showed that the variant causes large reductions (98%) in TMEM237 transcripts and fibroblasts with the variant had dysregulated Wnt signaling. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial aplasia of the vermis Pathogenic:1

Mar 29, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.25
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs199469707; hg19: chr2-202505638; COSMIC: COSV53804415; COSMIC: COSV53804415;