8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Position:

• chr8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant summary

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

The NM_153704.6(TMEM67):​c.224-6_224-3dupTTTT 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 0.00079 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0018 (4 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 4 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 67 AN: 85310 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000412

Gnomad AMI AF: 0.00345

Gnomad AMR AF: 0.000361

Gnomad ASJ AF: 0.00133

Gnomad EAS AF: 0.00130

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000261

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00175 AC: 958 AN: 547376 Hom.: 4 Cov.: 0 AF XY: 0.00184 AC XY: 533 AN XY: 289702

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.00478

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000785 AC: 67 AN: 85310 Hom.: 0 Cov.: 28 AF XY: 0.000871 AC XY: 35 AN XY: 40162

Gnomad4 AFR AF: 0.000411

Gnomad4 AMR AF: 0.000360

Gnomad4 ASJ AF: 0.00133

Gnomad4 EAS AF: 0.00131

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000261

Gnomad4 NFE AF: 0.00108

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;