rs3097427

Variant names:

• chr8-93782392-C-T
• rs3097427
• NM_153704.6:c.1066-3C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153704.6(TMEM67):​c.1066-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,603,638 control chromosomes in the GnomAD database, including 294,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32861 hom., cov: 31)
  • Exomes 𝑓: 0.60 (261660 hom.)
• Consequence: TMEM67 NM_153704.6 splice_region, intron
• Scores: Splicing: ADA: 0.0004581
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.0630

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-93782392-C-T is Benign according to our data. Variant chr8-93782392-C-T is described in ClinVar as [Benign]. Clinvar id is 96528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93782392-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.1066-3C>T		splice_region_variant, intron_variant	Intron 10 of 27	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.1066-3C>T		splice_region_variant, intron_variant	Intron 10 of 27	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98851 AN: 151840 Hom.: 32804 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.627

GnomAD3 exomes AF: 0.636 AC: 159161 AN: 250398 Hom.: 51711 AF XY: 0.627 AC XY: 84865 AN XY: 135254

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.836

Gnomad SAS exome AF: 0.609

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.578

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.597 AC: 866613 AN: 1451680 Hom.: 261660 Cov.: 31 AF XY: 0.596 AC XY: 430950 AN XY: 722606

Gnomad4 AFR exome AF: 0.777

Gnomad4 AMR exome AF: 0.716

Gnomad4 ASJ exome AF: 0.633

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.612

Gnomad4 FIN exome AF: 0.576

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.611

GnomAD4 genome AF: 0.651 AC: 98970 AN: 151958 Hom.: 32861 Cov.: 31 AF XY: 0.652 AC XY: 48440 AN XY: 74250

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.564

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.632

Alfa AF: 0.612 Hom.: 18661

Bravo AF: 0.664

Asia WGS AF: 0.704 AC: 2453 AN: 3478

EpiCase AF: 0.581

EpiControl AF: 0.588

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Aug 07, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 3 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 11 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 6 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COACH syndrome 1 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.010		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: rs3097427; hg19: chr8-94794620; COSMIC: COSV60043346; COSMIC: COSV60043346;