chr8-93804836-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_153704.6(TMEM67):c.2397T>C(p.Asp799Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,604,908 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 30)

Exomes 𝑓: 0.017 ( 256 hom. )

Consequence

TMEM67
NM_153704.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: 0.853

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 8-93804836-T-C is Benign according to our data. Variant chr8-93804836-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 126304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93804836-T-C is described in Lovd as [Benign]. Variant chr8-93804836-T-C is described in Lovd as [Likely_benign]. Variant chr8-93804836-T-C is described in Lovd as [Likely_pathogenic].

BP7

Synonymous conserved (PhyloP=0.853 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0126 (1924/152206) while in subpopulation SAS AF= 0.0199 (96/4822). AF 95% confidence interval is 0.0178. There are 19 homozygotes in gnomad4. There are 945 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.2397T>C	p.Asp799Asp	synonymous_variant	Exon 23 of 28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.2397T>C	p.Asp799Asp	synonymous_variant	Exon 23 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1924

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0153

AC:

3851

AN:

251028

Hom.:

AF XY:

0.0165

AC XY:

2245

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00843

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0234

Gnomad FIN exome

AF:

0.0138

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0169

AC:

24509

AN:

1452702

Hom.:

256

Cov.:

AF XY:

0.0171

AC XY:

12367

AN XY:

723304

show subpopulations

Gnomad4 AFR exome

AF:

0.00198

Gnomad4 AMR exome

AF:

0.00824

Gnomad4 ASJ exome

AF:

0.00948

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.0226

Gnomad4 FIN exome

AF:

0.0142

Gnomad4 NFE exome

AF:

0.0182

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0126

AC:

1924

AN:

152206

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

945

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0199

Gnomad4 FIN

AF:

0.0168

Gnomad4 NFE

AF:

0.0187

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0201

EpiControl

AF:

0.0198

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29127258) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMEM67: BP4, BP7, BS1, BS2 -

not specified

Benign:3

May 07, 2013

Genetic Services Laboratory, University of Chicago

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 14

Uncertain:1

Tolun Lab, Human Genetics Laboratory, Bogazici University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Meckel syndrome, type 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

- -

Kidney disorder

Benign:1

Sep 07, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 11

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1

Benign:1

Oct 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 6

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

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

-0.49

CADD

Benign

8.1

DANN

Benign

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over