Variant 11-125101303-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001258244.2(TMEM218):c.111G>T(p.Arg37Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,672 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMEM218
NM_001258244.2 missense, splice_region

Scores

Splicing: ADA: 0.9973

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.57

Variant links:

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]

TMEM218 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-125101303-C-A is Pathogenic according to our data. Variant chr11-125101303-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1677283.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM218	NM_001258244.2 linkuse as main transcript	c.111G>T	p.Arg37Ser	missense_variant, splice_region_variant	4/5	ENST00000682305.1	NP_001245173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM218	ENST00000682305.1 linkuse as main transcript	c.111G>T	p.Arg37Ser	missense_variant, splice_region_variant	4/5		NM_001258244.2	ENSP00000506979	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Joubert syndrome 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Apr 20, 2022

This variant is interpreted as likely pathogenic for Joubert syndrome 39, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Well-established functional studies show a deleterious effect (PS3). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;T;T;T;T;T;T;.;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.53

.;T;.;.;.;.;.;T;.;T;T

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.4

M;.;M;M;M;M;M;M;.;.;.

MutationTaster

Benign

0.98

D;D;D;D;D;D;D;D;D;D;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.7

D;N;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.010

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.044

D;D;D;D;D;D;D;D;.;.;.

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;D

Vest4

0.74

MutPred

0.38

.;Loss of sheet (P = 0.0181);.;.;.;.;.;.;.;.;.;

MVP

0.12

ClinPred

0.97

GERP RS

3.6

Varity_R

0.42

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.67

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: -47

DS_AL_spliceai

0.67

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over