rs772437766

Variant names:

• chr8-93755799-C-G
• rs772437766
• NM_153704.6:c.245C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-93755799-C-G
• chr8-93755799-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• COACH syndrome 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Meckel syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• nephronophthisis 11

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COACH syndrome 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Joubert syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Boichis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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, 7 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 chr8-93755798-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217715.
• 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 VariationId is 217714.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.245C>G	p.Pro82Arg	missense_variant	Exon 2 of 28	ENST00000453321.8	NP_714915.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8	c.245C>G	p.Pro82Arg	missense_variant	Exon 2 of 28	1	NM_153704.6	ENSP00000389998.3

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

African (AFR) AF: 0.00 AC: 0 AN: 28624

American (AMR) AF: 0.00 AC: 0 AN: 40592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23656

East Asian (EAS) AF: 0.00 AC: 0 AN: 36846

South Asian (SAS) AF: 0.00 AC: 0 AN: 75874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4648

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 963028

Other (OTH) AF: 0.00 AC: 0 AN: 53012

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

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

not provided Pathogenic:1

Sep 17, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1

Jan 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 29568536). ClinVar contains an entry for this variant (Variation ID: 217714). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

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;.
PhyloP100		3.2
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
Mutation Taster		=27/73	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs772437766; hg19: chr8-94768027;