rs3134031

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153704.6(TMEM67):c.1810A>G(p.Ile604Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,610,204 control chromosomes in the GnomAD database, including 305,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32347 hom., cov: 33)

Exomes 𝑓: 0.61 ( 273246 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.282

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.642796E-7).

BP6

Variant 8-93795937-A-G is Benign according to our data. Variant chr8-93795937-A-G is described in ClinVar as [Benign]. Clinvar id is 126301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93795937-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.1810A>G	p.Ile604Val	missense_variant	18/28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.1810A>G	p.Ile604Val	missense_variant	18/28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98564

AN:

152010

Hom.:

32297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.727

Gnomad AMI

AF:

0.684

Gnomad AMR

AF:

0.680

Gnomad ASJ

AF:

0.660

Gnomad EAS

AF:

0.731

Gnomad SAS

AF:

0.643

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.599

Gnomad OTH

AF:

0.630

GnomAD3 exomes

AF:

0.640

AC:

160774

AN:

251218

Hom.:

52192

AF XY:

0.634

AC XY:

86047

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.734

Gnomad AMR exome

AF:

0.740

Gnomad ASJ exome

AF:

0.660

Gnomad EAS exome

AF:

0.734

Gnomad SAS exome

AF:

0.623

Gnomad FIN exome

AF:

0.573

Gnomad NFE exome

AF:

0.597

Gnomad OTH exome

AF:

0.628

GnomAD4 exome

AF:

0.610

AC:

889740

AN:

1458076

Hom.:

273246

Cov.:

AF XY:

0.610

AC XY:

442352

AN XY:

725528

show subpopulations

Gnomad4 AFR exome

AF:

0.738

Gnomad4 AMR exome

AF:

0.730

Gnomad4 ASJ exome

AF:

0.663

Gnomad4 EAS exome

AF:

0.722

Gnomad4 SAS exome

AF:

0.625

Gnomad4 FIN exome

AF:

0.579

Gnomad4 NFE exome

AF:

0.596

Gnomad4 OTH exome

AF:

0.618

GnomAD4 genome

AF:

0.649

AC:

98676

AN:

152128

Hom.:

32347

Cov.:

AF XY:

0.649

AC XY:

48260

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.727

Gnomad4 AMR

AF:

0.680

Gnomad4 ASJ

AF:

0.660

Gnomad4 EAS

AF:

0.730

Gnomad4 SAS

AF:

0.643

Gnomad4 FIN

AF:

0.572

Gnomad4 NFE

AF:

0.599

Gnomad4 OTH

AF:

0.635

Alfa

AF:

0.612

Hom.:

69815

Bravo

AF:

0.660

TwinsUK

AF:

0.601

AC:

2229

ALSPAC

AF:

0.608

AC:

2344

ESP6500AA

AF:

0.729

AC:

3211

ESP6500EA

AF:

0.595

AC:

5117

ExAC

AF:

0.637

AC:

77325

Asia WGS

AF:

0.670

AC:

2334

AN:

3476

EpiCase

AF:

0.599

EpiControl

AF:

0.608

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Meckel syndrome, type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Nephronophthisis 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Joubert syndrome 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

COACH syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.9

DANN

Benign

0.71

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.058

T;T

MetaRNN

Benign

8.6e-7

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.5

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

0.39

N;N

REVEL

Benign

0.17

Sift

Benign

0.48

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;.

Vest4

0.020

MPC

0.097

ClinPred

0.00053

GERP RS

0.32

Varity_R

0.026

gMVP

0.19

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