rs1064792983

Positions:

• chr8-93803675-TATGAGTAATGTAA-TGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The ENST00000453321.8(TMEM67):​c.2314_2322+4delinsGG variant causes a splice donor, splice donor region, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM67 ENST00000453321.8 splice_donor, splice_donor_region, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026773762 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of -7, new splice context is: tggGTactt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-93803676-ATGAGTAATGTAA-GG is Pathogenic according to our data. Variant chr8-93803676-ATGAGTAATGTAA-GG is described in ClinVar as [Pathogenic]. Clinvar id is 411583.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.2314_2322+4delinsGG		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	22/28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.2314_2322+4delinsGG		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	22/28	1	NM_153704.6	ENSP00000389998	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

Nov 03, 2023

This variant results in the deletion of part of exon 22 (c.2314_2322+4delinsGG) of the TMEM67 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Meckel-Gruber syndrome (PMID: 17160906). 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 2315_2323+4del13insGG. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1064792983; hg19: chr8-94815904;