8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTT

Position:

• chr8-93755751-CTTTTTTTTTTTT-CTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_153704.6(TMEM67):​c.224-4_224-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 620,700 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (3 hom., cov: 28)
  • Exomes 𝑓: 0.035 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 Benign. Variant got -10 ACMG points.

• BP6: Variant 8-93755751-CTT-C is Benign according to our data. Variant chr8-93755751-CTT-C is described in ClinVar as [Benign]. Clinvar id is 126303.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-93755751-CTT-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 579 AN: 85310 Hom.: 3 Cov.: 28

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00277

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000326

Gnomad SAS AF: 0.00117

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00592

GnomAD4 exome AF: 0.0351 AC: 18809 AN: 535390 Hom.: 0 AF XY: 0.0345 AC XY: 9765 AN XY: 283028

Gnomad4 AFR exome AF: 0.0855

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.0554

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0331

Gnomad4 OTH exome AF: 0.0483

GnomAD4 genome AF: 0.00679 AC: 579 AN: 85310 Hom.: 3 Cov.: 28 AF XY: 0.00700 AC XY: 281 AN XY: 40162

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.00277

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000327

Gnomad4 SAS AF: 0.00118

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00591

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 03, 2013

- -

TMEM67-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2024

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

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;