rs387907133

Variant names:

• chr11-61368600-C-T
• rs387907133
• NM_016464.5:c.380C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_016464.5(TMEM138):​c.380C>T​(p.Ala127Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A127S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM138 NM_016464.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.08
• Publications: 5 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: Pathogenic. The variant received 14 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, 4 uncertain in NM_016464.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 11-61368600-C-T is Pathogenic according to our data. Variant chr11-61368600-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016464.5. 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
	TMEM138	NM_016464.5	MANE Select	c.380C>T	p.Ala127Val	missense	Exon 5 of 5	NP_057548.1
	TMEM138	NM_001330281.2		c.206C>T	p.Ala69Val	missense	Exon 5 of 5	NP_001317210.1
	TMEM138	NM_001441180.1		c.377C>T	p.Ala126Val	missense splice_region	Exon 5 of 5	NP_001428109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM138	ENST00000278826.11	TSL:1 MANE Select	c.380C>T	p.Ala127Val	missense	Exon 5 of 5	ENSP00000278826.5
	TMEM138	ENST00000543594.6	TSL:1	n.*591C>T		non_coding_transcript_exon	Exon 5 of 5	ENSP00000509354.1
	TMEM138	ENST00000542946.2	TSL:1	c.*2366C>T		3_prime_UTR	Exon 3 of 3	ENSP00000445792.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250830 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457918 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725596

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108872

Other (OTH) AF: 0.0000166 AC: 1 AN: 60262

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Joubert syndrome 16 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.44		Loss of methylation at R124 (P = 0.1898)
MVP		0.96
MPC		1.2
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.78
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs387907133; hg19: chr11-61136072;