8-93755799-C-G

Position:

• chr8-93755799-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_153704.6(TMEM67):​c.245C>G​(p.Pro82Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000783 in 1,277,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P82S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.24

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-93755798-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217715.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 8-93755799-C-G is Pathogenic according to our data. Variant chr8-93755799-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217714.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}. Variant chr8-93755799-C-G is described in Lovd as [Pathogenic]. Variant chr8-93755799-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.245C>G	p.Pro82Arg	missense_variant	2/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.245C>G	p.Pro82Arg	missense_variant	2/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.83e-7 AC: 1 AN: 1277496 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 640562

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: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Joubert syndrome 6 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Joubert syndrome 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:19574260). -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro82 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 19574260, 29568536), which suggests that this may be a clinically significant amino acid residue. 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: 217714). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 29568536). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 82 of the TMEM67 protein (p.Pro82Arg). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2015

The P82R variant has been reported previously in combination with the M252T variant in individuals withCOACH syndrome and Joubert syndrome related disorder (JSRD) without clinically apparent liver disease(Doherty et al., 2010). It was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations. The P82R variant is a non-conservative amino acid substitution, which is likely to impactsecondary protein structure as these residues differ in polarity, charge, size and/or other properties. Thissubstitution occurs at a position that is conserved across species. Additionally, a different missense variant atthe same residue (P82S) and in a nearby residue (N90K) have been reported in association with TMEM67-related disorders, supporting the functional importance of this region of the protein (Doherty et al., 2010;Iannicelli et al., 2010). We interpret P82R as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N;D
REVEL	Uncertain	0.40
Sift	Benign	0.068	T;D
Sift4G	Benign	0.32	T;D
Polyphen		0.086	B;.
Vest4		0.92
MutPred		0.64		Gain of solvent accessibility (P = 0.1045);Gain of solvent accessibility (P = 0.1045);
MVP		0.86
MPC		0.20
ClinPred		0.76	D
GERP RS		5.0
Varity_R		0.14
gMVP		0.81

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

Other links and lift over

dbSNP: rs772437766; hg19: chr8-94768027;