11-125102216-C-A

Position:

• chr11-125102216-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001258244.2(TMEM218):​c.26G>T​(p.Gly9Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM218 NM_001258244.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.31

Genes affected

TMEM218 (HGNC:27344): (transmembrane protein 218) Predicted to be located in cilium. Predicted to be integral component of membrane. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 11-125102216-C-A is Pathogenic according to our data. Variant chr11-125102216-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 983528.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM218	NM_001258244.2	c.26G>T	p.Gly9Val	missense_variant	3/5	ENST00000682305.1	NP_001245173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM218	ENST00000682305.1	c.26G>T	p.Gly9Val	missense_variant	3/5		NM_001258244.2	ENSP00000506979.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Joubert syndrome 39 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 12, 2021

- -

Familial aplasia of the vermis Pathogenic:1

Pathogenic, no assertion criteria provided

research

UW Hindbrain Malformation Research Program, University of Washington

Nov 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.33	T;.;.;T;T;T;T;.;T;T;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	.;T;.;.;.;.;.;T;.;D;.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.5	M;.;.;M;M;M;M;.;M;M;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.9	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;.;.;.
Polyphen		1.0	D;D;.;D;D;D;D;.;D;D;D;D;D
Vest4		0.90
MutPred		0.34		Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);Loss of disorder (P = 0.057);
MVP		0.16
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.96

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: rs1950967763; hg19: chr11-124972112;