rs762543032

Variant names:

• chr8-93755798-C-T
• rs762543032
• NM_153704.6:c.244C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_153704.6(TMEM67):​c.244C>T​(p.Pro82Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000527 in 1,138,356 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P82R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.81
• Publications: 4 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 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, 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 chr8-93755799-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217714.
• PP5: Variant 8-93755798-C-T is Pathogenic according to our data. Variant chr8-93755798-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217715.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2837273). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6	c.244C>T	p.Pro82Ser	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.244C>T	p.Pro82Ser	missense_variant	Exon 2 of 28	1	NM_153704.6	ENSP00000389998.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 230108 AF XY: 0.00000803

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000599

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000527 AC: 6 AN: 1138356 Hom.: 0 Cov.: 26 AF XY: 0.00000871 AC XY: 5 AN XY: 574380

African (AFR) AF: 0.00 AC: 0 AN: 26312

American (AMR) AF: 0.00 AC: 0 AN: 38856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21570

East Asian (EAS) AF: 0.000150 AC: 5 AN: 33392

South Asian (SAS) AF: 0.00 AC: 0 AN: 72572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 845800

Other (OTH) AF: 0.0000212 AC: 1 AN: 47124

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Joubert syndrome 6 Pathogenic:2

Aug 30, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.79 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TMEM67 related disorder (ClinVar ID: VCV000217715 /PMID: 19574260).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset).A different missense change at the same codon (p.Pro82Arg) has been reported to be associated with TMEM67 related disorder (ClinVar ID: VCV000217714 /PMID: 19574260). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not specified Uncertain:1

Aug 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMEM67 c.244C>T (p.Pro82Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 230108 control chromosomes (gnomAD). c.244C>T has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders (e.g. Doherty_2010, Sakamoto_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19574260, 36305856). One ClinVar submitter has assessed the variant since 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		4.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.25
Sift	Benign	0.16	T;T
Sift4G	Benign	0.34	T;D
Vest4		0.57
ClinPred		0.26	T
GERP RS		5.9
Varity_R		0.10
gMVP		0.75
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs762543032; hg19: chr8-94768026;