rs1064792983

Variant names:

• chr8-93803676-ATGAGTAATGTAA-GG
• rs1064792983
• NM_153704.6:c.2314_2322+4delATGAGTAATGTAAinsGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_153704.6(TMEM67):​c.2314_2322+4delATGAGTAATGTAAinsGG​(p.Met772GlyfsTer17) variant causes a frameshift, splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM67 NM_153704.6 frameshift, splice_donor, missense, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• COACH syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Meckel syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• nephronophthisis 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COACH syndrome 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Joubert syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Boichis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-93803676-ATGAGTAATGTAA-GG is Pathogenic according to our data. Variant chr8-93803676-ATGAGTAATGTAA-GG is described in ClinVar as Pathogenic. ClinVar VariationId is 411583.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153704.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.2314_2322+4delATGAGTAATGTAAinsGG	p.Met772GlyfsTer17	frameshift splice_donor missense splice_region intron	Exon 22 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.2071_2079+4delATGAGTAATGTAAinsGG	p.Met691GlyfsTer17	frameshift splice_donor missense splice_region intron	Exon 23 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.2335_2343+4delATGAGTAATGTAAinsGG		splice_donor splice_region intron non_coding_transcript_exon	Exon 22 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2314_2322+4delATGAGTAATGTAAinsGG	p.Met772GlyfsTer17	frameshift splice_donor missense splice_region intron	Exon 22 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.2314_2322+4delATGAGTAATGTAAinsGG	p.Met772GlyfsTer4	frameshift splice_donor missense splice_region intron	Exon 22 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.1452_1460+4delATGAGTAATGTAAinsGG		splice_donor splice_region intron non_coding_transcript_exon	Exon 13 of 17

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:Joubert syndrome Pathogenic:1

Nov 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

Other links and lift over

dbSNP: rs1064792983; hg19: chr8-94815904;