rs386834190

chr8-93755775-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PP3_Moderate PP5_Very_Strong

The NM_153704.6(TMEM67):c.224-2del variant causes a splice acceptor change. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM67 NM_153704.6 splice_acceptor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.029451137 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.6, offset of 24, new splice context is: ttcatgtgtatgtctaccAGgat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-93755775-TA-T is Pathogenic according to our data. Variant chr8-93755775-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 56771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93755775-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.224-2del		splice_acceptor_variant		ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.224-2del		splice_acceptor_variant		1	NM_153704.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13 AN: 144458 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.000296

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: 0.0000297

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000410 AC: 466 AN: 1136608 Hom.: 0 Cov.: 8 AF XY: 0.000421 AC XY: 242 AN XY: 574986

Gnomad4 AFR exome AF: 0.000888

Gnomad4 AMR exome AF: 0.0000618

Gnomad4 ASJ exome AF: 0.0000443

Gnomad4 EAS exome AF: 0.0000551

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000403

Gnomad4 NFE exome AF: 0.000479

Gnomad4 OTH exome AF: 0.000455

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000899 AC: 13 AN: 144550 Hom.: 0 Cov.: 0 AF XY: 0.000142 AC XY: 10 AN XY: 70388

Gnomad4 AFR AF: 0.000296

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: 0.0000297

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel syndrome, type 3 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

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

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2023

This sequence change affects a splice site in intron 1 of the TMEM67 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of TMEM67-related conditions (PMID: 17377820). This variant is also known as IVS1-2delA. ClinVar contains an entry for this variant (Variation ID: 56771). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 17377820). The resulting mRNA is expected to undergo nonsense-mediated decay. 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

Fulgent Genetics, Fulgent Genetics

Sep 22, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 27
DS_AL_spliceai		0.99		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs386834190; hg19: chr8-94768003; COSMIC: COSV60035525;