rs386834193

chr8-93804796-G-Achr8-93804796-G-Cchr8-93804796-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_153704.6(TMEM67):c.2357G>A(p.Gly786Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,454,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G786A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.47

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 NM_153704.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-93804796-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 684615.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 8-93804796-G-A is Pathogenic according to our data. Variant chr8-93804796-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56774.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr8-93804796-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.2357G>A	p.Gly786Glu	missense_variant	23/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.2357G>A	p.Gly786Glu	missense_variant	23/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250790 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135598

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1454900 Hom.: 0 Cov.: 28 AF XY: 0.0000193 AC XY: 14 AN XY: 724342

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: 0.0000226

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.000107 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 786 of the TMEM67 protein (p.Gly786Glu). This variant is present in population databases (rs386834193, gnomAD 0.007%). This missense change has been observed in individual(s) with Meckel syndrome (PMID: 20232449). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56774). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly786 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31411728). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Meckel syndrome, type 3 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

-

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MVP		1.0
MPC		0.64
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.35		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs386834193; hg19: chr8-94817024; COSMIC: COSV60038677;