rs386834190

Variant names:

• chr8-93755775-TA-T
• rs386834190
• NM_153704.6:c.224-2delA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_153704.6(TMEM67):​c.224-2delA variant causes a splice acceptor, intron 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, intron
• 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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02978581 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.
• 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 rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.224-2delA		splice_acceptor_variant, intron_variant	Intron 1 of 27	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.224-2delA		splice_acceptor_variant, intron_variant	Intron 1 of 27	1	NM_153704.6	ENSP00000389998.3

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

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 56771). This variant is also known as IVS1-2delA. Disruption of this splice site has been observed in individual(s) with clinical features of TMEM67-related conditions (PMID: 17377820). This variant is not present in population databases (gnomAD no frequency). 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. -

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

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;