8-93755751-C-CTT

Position:

• chr8-93755751-C-CTT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1 BS1 BS2

The NM_153704.6(TMEM67):​c.224-4_224-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 629,278 control chromosomes in the GnomAD database, including 19 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 28)
  • Exomes 𝑓: 0.015 (19 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.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0149 (8100/543964) while in subpopulation SAS AF= 0.0314 (1321/42132). AF 95% confidence interval is 0.0299. There are 19 homozygotes in gnomad4_exome. There are 4471 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.224-4_224-3dupTT		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.224-4_224-3dupTT		splice_acceptor_variant, intron_variant		1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 222 AN: 85314 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00206

Gnomad AMI AF: 0.00345

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.00178

Gnomad EAS AF: 0.00293

Gnomad SAS AF: 0.00156

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0149 AC: 8100 AN: 543964 Hom.: 19 Cov.: 0 AF XY: 0.0155 AC XY: 4471 AN XY: 287794

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.0140

Gnomad4 SAS exome AF: 0.0314

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.00260 AC: 222 AN: 85314 Hom.: 0 Cov.: 28 AF XY: 0.00251 AC XY: 101 AN XY: 40164

Gnomad4 AFR AF: 0.00206

Gnomad4 AMR AF: 0.00108

Gnomad4 ASJ AF: 0.00178

Gnomad4 EAS AF: 0.00294

Gnomad4 SAS AF: 0.00157

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00359

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;