rs35245221

chr11-61366177-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016464.5(TMEM138):c.261G>A(p.Val87=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,614,164 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (121 hom.)
• Consequence: TMEM138 NM_016464.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0440

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-61366177-G-A is Benign according to our data. Variant chr11-61366177-G-A is described in ClinVar as [Benign]. Clinvar id is 130586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61366177-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.044 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM138	NM_016464.5	c.261G>A	p.Val87=	synonymous_variant	3/5	ENST00000278826.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM138	ENST00000278826.11	c.261G>A	p.Val87=	synonymous_variant	3/5	1	NM_016464.5	P1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2755 AN: 152200 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00834 AC: 2096 AN: 251440 Hom.: 43 AF XY: 0.00818 AC XY: 1111 AN XY: 135896

Gnomad AFR exome AF: 0.0558

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00364

Gnomad SAS exome AF: 0.0215

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00422 AC: 6175 AN: 1461846 Hom.: 121 Cov.: 30 AF XY: 0.00457 AC XY: 3323 AN XY: 727218

Gnomad4 AFR exome AF: 0.0589

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00563

Gnomad4 EAS exome AF: 0.00161

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.00937

GnomAD4 genome AF: 0.0182 AC: 2767 AN: 152318 Hom.: 76 Cov.: 31 AF XY: 0.0184 AC XY: 1369 AN XY: 74478

Gnomad4 AFR AF: 0.0563

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0104 Hom.: 9

Bravo AF: 0.0196

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00308

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 16 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	7.6
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35245221; hg19: chr11-61133649;