8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Position:

• chr8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_153704.6(TMEM67):​c.224-5_224-3dupTTT 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 0.0017 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0042 (13 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 Uncertain_significance. Variant got 4 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.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.224-5_224-3dupTTT		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.224-5_224-3dupTTT		splice_acceptor_variant, intron_variant		1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 148 AN: 85292 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00692

Gnomad AMR AF: 0.000842

Gnomad ASJ AF: 0.00222

Gnomad EAS AF: 0.00163

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000521

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000849

GnomAD4 exome AF: 0.00416 AC: 2276 AN: 546700 Hom.: 13 Cov.: 0 AF XY: 0.00443 AC XY: 1283 AN XY: 289328

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00446

Gnomad4 EAS exome AF: 0.00318

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00323

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00174 AC: 148 AN: 85292 Hom.: 0 Cov.: 28 AF XY: 0.00164 AC XY: 66 AN XY: 40158

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.000841

Gnomad4 ASJ AF: 0.00222

Gnomad4 EAS AF: 0.00163

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000521

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.000847

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;