rs115660279

Variant names:

• chr8-93755100-T-C
• rs115660279
• NM_153704.6:c.186T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6 BP7 BS2

The NM_153704.6(TMEM67):​c.186T>C​(p.Cys62Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,202 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: TMEM67 NM_153704.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: -0.0110
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• COACH syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Meckel syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• nephronophthisis 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COACH syndrome 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Joubert syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Boichis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: REVEL computational evidence supports a deleterious effect, 0.711
• BP6: Variant 8-93755100-T-C is Benign according to our data. Variant chr8-93755100-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215970.
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.186T>C	p.Cys62Cys	synonymous_variant	Exon 1 of 28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.186T>C	p.Cys62Cys	synonymous_variant	Exon 1 of 28	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00126 AC: 317 AN: 251484 AF XY: 0.00118

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00187 AC: 2737 AN: 1461886 Hom.: 3 Cov.: 31 AF XY: 0.00179 AC XY: 1303 AN XY: 727242

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00631 AC: 165 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00210 AC: 2335 AN: 1112006

Other (OTH) AF: 0.00185 AC: 112 AN: 60396

GnomAD4 genome AF: 0.00140 AC: 214 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74494

African (AFR) AF: 0.000529 AC: 22 AN: 41556

American (AMR) AF: 0.00242 AC: 37 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68034

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00165

EpiCase AF: 0.00115

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17397051, 23736532) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMEM67: BP4, BP7 -

Meckel syndrome, type 3 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis 11 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Joubert syndrome 6 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.67
CADD	Benign	9.3
DANN	Benign	0.65
PhyloP100		-0.011
PromoterAI		0.019	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs115660279; hg19: chr8-94767328;