rs797046045

Positions:

chr8-93755851-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_153704.6(TMEM67):c.297G>T(p.Lys99Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000007 in 142,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.47

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:

TMEM67 (HGNC:):

TMEM67 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-93755851-G-T is Pathogenic according to our data. Variant chr8-93755851-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212409.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr8-93755851-G-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.3361599). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.297G>T	p.Lys99Asn	missense_variant	2/28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.297G>T	p.Lys99Asn	missense_variant	2/28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.00000700

AC:

AN:

142808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1379688

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685540

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000700

AC:

AN:

142808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68898

show subpopulations

Gnomad4 AFR

AF:

0.0000260

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2022

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 99 of the TMEM67 protein (p.Lys99Asn). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function. ClinVar contains an entry for this variant (Variation ID: 212409). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 26092869). This variant is present in population databases (rs797046045, gnomAD 0.01%). -

COACH syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Jul 28, 2023

This sequence variant is a single nucleotide substitution (G>T) at position 297 of the coding sequence of the TMEM67 gene that results in a lysine to asparagine amino acid change at residue 99 of the transmembrane protein 67 protein. This is a previously reported variant (ClinVar 212409) that has not been observed in the literature, save for reports of the proband (PMID: 19574260, 28125082), in which case it was reported in trans with a pathogenic TMEM67 variant. This variant is present in 1 of 30502 alleles (0.0033%) in the gnomAD population dataset. Bioinformatic tools are inconclusive if this amino acid change will be damaging or tolerated, and the Lys99 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PM3, PP2, PP4 -

Joubert syndrome 6

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.062

T;D

Sift4G

Uncertain

0.038

D;D

Polyphen

0.98

D;.

Vest4

0.87

MutPred

0.49

Loss of methylation at K99 (P = 9e-04);Loss of methylation at K99 (P = 9e-04);

MVP

0.74

MPC

0.25

ClinPred

0.96

GERP RS

4.9

Varity_R

0.22

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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