8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTT

Position:

• chr8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_153704.6(TMEM67):​c.224-12_224-3dupTTTTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 633,116 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000069 (0 hom.)
• 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 Pathogenic. Variant got 10 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.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.224-12_224-3dupTTTTTTTTTT		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.224-12_224-3dupTTTTTTTTTT		splice_acceptor_variant, intron_variant		1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.0000117 AC: 1 AN: 85340 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

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: 0.0000241

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000694 AC: 38 AN: 547776 Hom.: 0 Cov.: 0 AF XY: 0.0000448 AC XY: 13 AN XY: 289910

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000147

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.0000847

Gnomad4 SAS exome AF: 0.000212

Gnomad4 FIN exome AF: 0.0000913

Gnomad4 NFE exome AF: 0.0000503

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000117 AC: 1 AN: 85340 Hom.: 0 Cov.: 28 AF XY: 0.0000249 AC XY: 1 AN XY: 40174

Gnomad4 AFR AF: 0.00

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: 0.0000241

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;