rs117195541

Variant names:

• chr8-93804836-T-C
• rs117195541
• NM_153704.6:c.2397T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 0.853

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 -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	c.2397T>C	p.Asp799Asp	synonymous_variant	Exon 23 of 28	ENST00000453321.8	NP_714915.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1924 AN: 152088 Hom.: 19 Cov.: 30

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.: 37 AF XY: 0.0165 AC XY: 2245 AN XY: 135712

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.: 27 AF XY: 0.0171 AC XY: 12367 AN XY: 723304

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.: 19 Cov.: 30 AF XY: 0.0127 AC XY: 945 AN XY: 74414

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.: 15

Bravo AF: 0.0116

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0201

EpiControl AF: 0.0198

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

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

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 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

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. -

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

Other links and lift over

dbSNP: rs117195541; hg19: chr8-94817064;