chr8-93755751-C-CT

Position:

• chr8-93755751-C-CT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1 BA1

The NM_153704.6(TMEM67):​c.224-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0764 in 627,798 control chromosomes in the GnomAD database, including 175 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.034 (85 hom., cov: 28)
  • Exomes 𝑓: 0.083 (90 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 Uncertain_significance. Variant got 0 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.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0345 AC: 2939 AN: 85236 Hom.: 85 Cov.: 28

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.0224

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0347

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.00417

Gnomad MID AF: 0.0317

Gnomad NFE AF: 0.0410

Gnomad OTH AF: 0.0305

GnomAD4 exome AF: 0.0830 AC: 45046 AN: 542562 Hom.: 90 Cov.: 0 AF XY: 0.0858 AC XY: 24609 AN XY: 286824

Gnomad4 AFR exome AF: 0.0690

Gnomad4 AMR exome AF: 0.0714

Gnomad4 ASJ exome AF: 0.0949

Gnomad4 EAS exome AF: 0.0984

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.0763

Gnomad4 NFE exome AF: 0.0771

Gnomad4 OTH exome AF: 0.0944

GnomAD4 genome AF: 0.0345 AC: 2940 AN: 85236 Hom.: 85 Cov.: 28 AF XY: 0.0315 AC XY: 1263 AN XY: 40120

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0347

Gnomad4 EAS AF: 0.0357

Gnomad4 SAS AF: 0.0282

Gnomad4 FIN AF: 0.00417

Gnomad4 NFE AF: 0.0410

Gnomad4 OTH AF: 0.0305

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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;