rs35765535

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_153704.6(TMEM67):c.1309C>G(p.Leu437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,613,922 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 9 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 2.25

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_153704.6

BP4

Computational evidence support a benign effect (MetaRNN=0.018277079).

BP6

Variant 8-93786243-C-G is Benign according to our data. Variant chr8-93786243-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126299.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6}. Variant chr8-93786243-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.1309C>G	p.Leu437Val	missense_variant	Exon 13 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.1309C>G	p.Leu437Val	missense_variant	Exon 13 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.00207

AC:

315

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00297

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00201

AC:

504

AN:

251080

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.000680

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00264

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00322

AC:

4712

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00311

AC XY:

2264

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.00165

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.0000383

AC:

AN:

26132

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39680

Gnomad4 SAS exome

AF:

0.000661

AC:

AN:

86250

Gnomad4 FIN exome

AF:

0.00277

AC:

148

AN:

53358

Gnomad4 NFE exome

AF:

0.00383

AC:

4264

AN:

1111886

Gnomad4 Remaining exome

AF:

0.00245

AC:

148

AN:

60390

Heterozygous variant carriers

227

454

682

909

1136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00207

AC:

315

AN:

152258

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000770

AC:

0.000769934

AN:

0.000769934

Gnomad4 AMR

AF:

0.00216

AC:

0.0021594

AN:

0.0021594

Gnomad4 ASJ

AF:

0.000289

AC:

0.000288517

AN:

0.000288517

Gnomad4 EAS

AF:

0.000193

AC:

0.000192901

AN:

0.000192901

Gnomad4 SAS

AF:

0.000829

AC:

0.000829187

AN:

0.000829187

Gnomad4 FIN

AF:

0.00368

AC:

0.00367786

AN:

0.00367786

Gnomad4 NFE

AF:

0.00297

AC:

0.0029698

AN:

0.0029698

Gnomad4 OTH

AF:

0.00142

AC:

0.00142045

AN:

0.00142045

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00270

Hom.:

Bravo

AF:

0.00207

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00188

AC:

228

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMEM67: BS2 -

Jul 31, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

Mar 15, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19574260) -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2014

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TMEM67 c.1309C>G (p.Leu437Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251080 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.75 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM67 causing Joubert Syndrome And Related Disorders phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.1309C>G in individuals affected with Joubert Syndrome And Related Disorders has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (example, Leitch_2008). These results showed no damaging effect of this variant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Meckel syndrome, type 3

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.084

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Uncertain

2.2

.;M;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.61

N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.19

T;T;T;D

Sift4G

Uncertain

0.035

D;T;T;T

Polyphen

0.026

.;B;.;.

Vest4

0.79, 0.77

MVP

0.97

MPC

0.12

ClinPred

0.015

GERP RS

4.8

Varity_R

0.14

gMVP

0.51

Mutation Taster

=85/15

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -20

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