8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTT

Position:

• chr8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_153704.6(TMEM67):​c.224-11_224-3dupTTTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000089 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM67 NM_153704.6 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.723

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.224-11_224-3dupTTTTTTTTT		splice_acceptor_variant, intron_variant		ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.224-11_224-3dupTTTTTTTTT		splice_acceptor_variant, intron_variant		1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7 AN: 85334 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.0000457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000120

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: 0.000120

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000895 AC: 49 AN: 547760 Hom.: 0 Cov.: 0 AF XY: 0.000114 AC XY: 33 AN XY: 289898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000795

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000820 AC: 7 AN: 85334 Hom.: 0 Cov.: 28 AF XY: 0.0000747 AC XY: 3 AN XY: 40170

Gnomad4 AFR AF: 0.0000457

Gnomad4 AMR AF: 0.000120

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000120

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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: rs587779735; hg19: chr8-94767979;