8-93797456-C-G

Variant names:

• chr8-93797456-C-G
• rs863225238
• NM_153704.6:c.2086C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_153704.6(TMEM67):​c.2086C>G​(p.Leu696Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L696F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.55
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-93797456-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217729.
• PP5: Variant 8-93797456-C-G is Pathogenic according to our data. Variant chr8-93797456-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1474211.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153704.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.2086C>G	p.Leu696Val	missense	Exon 20 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.1843C>G	p.Leu615Val	missense	Exon 21 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.2107C>G		non_coding_transcript_exon	Exon 20 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2086C>G	p.Leu696Val	missense	Exon 20 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.2086C>G	p.Leu696Val	missense	Exon 20 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.1224C>G		non_coding_transcript_exon	Exon 11 of 17

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.10
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.57
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.50	P
Vest4		0.44
MutPred		0.73		Gain of catalytic residue at L696 (P = 0.1427)
MVP		0.99
MPC		0.13
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.24
gMVP		0.70
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs863225238; hg19: chr8-94809684;