rs35793208

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_153704.6(TMEM67):c.781G>A(p.Asp261Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,613,938 control chromosomes in the GnomAD database, including 219 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D261D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 16 hom., cov: 32)

Exomes 𝑓: 0.014 ( 203 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 3.43

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 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=0.0037896931).

BP6

Variant 8-93780659-G-A is Benign according to our data. Variant chr8-93780659-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 126307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93780659-G-A is described in Lovd as [Benign]. Variant chr8-93780659-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0119 (1814/152172) while in subpopulation SAS AF= 0.0264 (127/4818). AF 95% confidence interval is 0.0226. There are 16 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.781G>A	p.Asp261Asn	missense_variant	8/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.781G>A	p.Asp261Asn	missense_variant	8/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1814

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0261

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0151

AC:

3784

AN:

251334

Hom.:

AF XY:

0.0163

AC XY:

2217

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00809

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0242

Gnomad FIN exome

AF:

0.0341

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0137

AC:

19994

AN:

1461766

Hom.:

203

Cov.:

AF XY:

0.0143

AC XY:

10398

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.00897

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0250

Gnomad4 FIN exome

AF:

0.0318

Gnomad4 NFE exome

AF:

0.0130

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0119

AC:

1814

AN:

152172

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

951

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00268

Gnomad4 AMR

AF:

0.0139

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0264

Gnomad4 FIN

AF:

0.0297

Gnomad4 NFE

AF:

0.0141

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0137

Hom.:

Bravo

AF:

0.00984

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0145

AC:

1761

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0146

EpiControl

AF:

0.0147

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TMEM67: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Meckel syndrome, type 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Benign

0.89

DEOGEN2

Benign

0.32

T;T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-0.38

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.53

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.62

T;T;T

Sift4G

Benign

0.74

T;T;T

Polyphen

0.0050

.;B;.

Vest4

0.026, 0.094

MPC

0.12

ClinPred

0.0022

GERP RS

2.8

Varity_R

0.037

gMVP

0.52

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