rs863225226

Positions:

• chr8-93758559-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_153704.6(TMEM67):​c.389C>G​(p.Pro130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P130P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.48

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_153704.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-93758559-C-G is Pathogenic according to our data. Variant chr8-93758559-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 217709.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in UniProt as null. Variant chr8-93758559-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM67	NM_153704.6	c.389C>G	p.Pro130Arg	missense_variant	3/28	ENST00000453321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM67	ENST00000453321.8	c.389C>G	p.Pro130Arg	missense_variant	3/28	1	NM_153704.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	-0.060	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.021	D;D;T
Polyphen		0.97	.;D;.
Vest4		0.82
MutPred		0.54		.;Gain of solvent accessibility (P = 0.1422);Gain of solvent accessibility (P = 0.1422);
MVP		0.87
MPC		0.27
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.28
gMVP		0.90

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: rs863225226; hg19: chr8-94770787;