dbSNP rs386834192: TMEM67:c.2322+2dupT (chr8-93803685-G-GT) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The ENST00000453321.8(TMEM67):c.2322+1_2322+2insT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,520,812 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

TMEM67
ENST00000453321.8 splice_donor, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 7.38

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.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027108435 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-93803685-G-GT is Pathogenic according to our data. Variant chr8-93803685-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56773.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.2322+2dupT		splice_region_variant, intron_variant	Intron 22 of 27	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.2322+1_2322+2insT		splice_donor_variant, intron_variant	Intron 22 of 27	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251108

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135746

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:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000358

AC:

AN:

1368686

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

686146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000428

Gnomad4 OTH exome

AF:

0.0000525

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00192

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome 6

Pathogenic:2

Feb 10, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous canonical splice site variant, NM_153704.5(TMEM67):c.2322+2dupT, has been identified in intron 22 of 27 of the TMEM67 gene. The conservation of this nucleotide was very high (UCSC, Phylop), and in silico tools consistently predict this variant to affect splicing (Human splicing Finder, Fruit fly, Netgene2). This duplication variant may result in a truncated protein; further testing via RNA studies are required to confirm if splicing is altered. The variant is present in the gnomAD database at a frequency of 0.00283% (8 heterozygotes, 0 homozygotes). The variant has been previously described as both a VUS and pathogenic in patients with Joubert syndrome (ClinVar). Subsequent analysis of parental samples indicated this variant was paternally inherited. Based on current information, this variant has been classified as PATHOGENIC. NB: This variant has been reclassified as PATHOGENIC due to confirmation of a pathogenic variant in trans. -

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Pathogenic:1

Jan 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 22 of the TMEM67 gene. It does not directly change the encoded amino acid sequence of the TMEM67 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs781071815, gnomAD 0.006%). This variant has been observed in individual(s) with Joubert syndrome and related disorders (PMID: 20232449, 26092869, 28497568). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2322+2dupT. ClinVar contains an entry for this variant (Variation ID: 56773). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Meckel syndrome, type 3

Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COACH syndrome 1

Pathogenic:1

Jul 28, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide duplication (dupT) at the +2 position of the intron 22 canonical splice donor site of the TMEM67 gene. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of TMEM67 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 56773). Aside from literature reports on the proband (PMID: 19574260, 28125082), this variant has additiolly been observed in trans with a second TMEM67 variant in multiple individuals affected by Joubert syndrome, Meckel syndrome, or other TMEM67-related disorders (PMID: 28497568, 26092869, 20232449); in one individual with suspected monogenic kidney disease, it was unclear if a second TMEM67 variant was present (PMID: 32939031). This variant is present in 8 of 282484 alleles (0.0028%) in the gnomAD population dataset. In a lymphoblastoid cell line derived from the proband which presumably carried the variant, splicing of exon 22 was not affected (PMID: 19574260). Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PS4, PVS1 -

not provided

Uncertain:1

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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