8-93755751-CTTTTTTTTTTTT-CTTTTTTT

Position:

• chr8-93755751-CTTTTTTTTTTTT-CTTTTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_153704.6(TMEM67):​c.224-7_224-3delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 632,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.28

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 8-93755751-CTTTTT-C is Benign according to our data. Variant chr8-93755751-CTTTTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 3034484.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.224-7_224-3delTTTTT		splice_region_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.224-7_224-3delTTTTT		splice_region_variant, intron_variant		1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.0000586 AC: 5 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: 0.000120

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000338 AC: 185 AN: 547430 Hom.: 0 AF XY: 0.000352 AC XY: 102 AN XY: 289740

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00165

Gnomad4 SAS exome AF: 0.0000941

Gnomad4 FIN exome AF: 0.000274

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000367

GnomAD4 genome AF: 0.0000586 AC: 5 AN: 85340 Hom.: 0 Cov.: 28 AF XY: 0.0000498 AC XY: 2 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: 0.000120

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TMEM67-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 20, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;