rs200329273

Positions:

chr8-93765410-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The ENST00000453321.8(TMEM67):c.511G>A(p.Val171Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,610,704 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

TMEM67
ENST00000453321.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.204

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000453321.8

BP4

Computational evidence support a benign effect (MetaRNN=0.03911823).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.511G>A	p.Val171Ile	missense_variant	5/28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.511G>A	p.Val171Ile	missense_variant	5/28	1	NM_153704.6	ENSP00000389998	P1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000271

AC:

AN:

251234

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000370

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000203

AC:

296

AN:

1458514

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

725594

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000138

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

Joubert syndrome 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 26, 2020

- -

TMEM67-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The TMEM67 c.511G>A variant is predicted to result in the amino acid substitution p.Val171Ile. To our knowledge, this variant has not been reported in the literature in association with disease. It was reported in a control individual from a large study of focal segmental glomerulosclerosis (Table S4, Wang. 2019. PubMed ID: 31308072). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.22

CADD

Benign

5.1

DANN

Benign

0.71

DEOGEN2

Benign

0.28

T;T;.;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.52

T;T;T;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.039

T;T;T;T

MetaSVM

Uncertain

-0.048

MutationAssessor

Benign

0.69

.;N;.;.

MutationTaster

Benign

0.95

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.090

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.47

T;T;T;T

Sift4G

Benign

0.39

T;T;T;T

Polyphen

0.28

.;B;.;.

Vest4

0.15, 0.16

MVP

0.80

MPC

0.095

ClinPred

0.021

GERP RS

-1.5

Varity_R

0.019

gMVP

0.25

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