rs387907134

Variant names:

• chr11-61367998-G-A
• rs387907134
• NM_016464.5:c.376G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61367998-G-A
• chr11-61367998-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_016464.5(TMEM138):​c.376G>A​(p.Ala126Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM138 NM_016464.5 missense, splice_region
• Scores: Splicing: ADA: 0.9974
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95
• Publications: 4 publications found

Genes affected

TMEM138 (HGNC:26944): (transmembrane protein 138) This gene encodes a multi-pass transmembrane protein. Reduced expression of this gene in mouse fibroblasts causes short cilia and failure of ciliogenesis. Expression of this gene is tightly coordinated with expression of the neighboring gene TMEM216. Mutations in this gene are associated with the autosomal recessive neurodevelopmental disorder Joubert Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

TMEM138 Gene-Disease associations (from GenCC):

• Joubert syndrome 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Joubert syndrome with oculorenal defect

  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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_016464.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-61367998-G-A is Pathogenic according to our data. Variant chr11-61367998-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31190.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM138	NM_016464.5	c.376G>A	p.Ala126Thr	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000278826.11	NP_057548.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM138	ENST00000278826.11	c.376G>A	p.Ala126Thr	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_016464.5	ENSP00000278826.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Joubert syndrome 16 Pathogenic:1

Feb 24, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.2	L;.
PhyloP100		8.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.91	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.17	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0070	B;.
Vest4		0.46
MutPred		0.45		Loss of stability (P = 0.1128);.;
MVP		0.97
MPC		0.40
ClinPred		0.85	D
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.11
gMVP		0.47
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 17
DS_DL_spliceai		0.55		Position offset: 0

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

Other links and lift over

dbSNP: rs387907134; hg19: chr11-61135470;