11-61366050-AG-GC

Variant names:

• chr11-61366050-AG-GC
• NM_016464.5:c.134_135delAGinsGC
• TMEM138 p.Gln45Arg

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS1 PP3

The NM_016464.5(TMEM138):​c.134_135delAGinsGC​(p.Gln45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM138 NM_016464.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.95
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS1: Transcript NM_016464.5 (TMEM138) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM138	NM_016464.5	MANE Select	c.134_135delAGinsGC	p.Gln45Arg	missense	N/A	NP_057548.1	Q9NPI0-1
	TMEM138	NM_001410999.1		c.134_135delAGinsGC	p.Gln45Arg	missense	N/A	NP_001397928.1	Q9NPI0-3
	TMEM138	NM_001441180.1		c.134_135delAGinsGC	p.Gln45Arg	missense	N/A	NP_001428109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM138	ENST00000278826.11	TSL:1 MANE Select	c.134_135delAGinsGC	p.Gln45Arg	missense	N/A	ENSP00000278826.5	Q9NPI0-1
	TMEM138	ENST00000542946.2	TSL:1	c.134_135delAGinsGC	p.Gln45Arg	missense	N/A	ENSP00000445792.1	Q9NPI0-2
	TMEM138	ENST00000534963.5	TSL:1	n.233_234delAGinsGC		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-61133522;