Genetic Variant TMEM138:c.*826T>C (chr11-61367060-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000542946.2(TMEM138):c.*826T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 152,146 control chromosomes in the GnomAD database, including 45,716 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.74 ( 45708 hom., cov: 31)

Exomes 𝑓: 0.86 ( 8 hom. )

Consequence

TMEM138
ENST00000542946.2 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.466

Publications

11 publications found

Variant links:

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

TMEM138 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM138	NM_016464.5 link	c.300+844T>C		intron_variant	Intron 3 of 4	ENST00000278826.11	NP_057548.1	Q9NPI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM138	ENST00000278826.11 link	c.300+844T>C		intron_variant	Intron 3 of 4	1	NM_016464.5	ENSP00000278826.5		Q9NPI0-1

Frequencies

GnomAD3 genomes

AF:

0.745

AC:

113234

AN:

152006

Hom.:

45711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.912

Gnomad AMR

AF:

0.850

Gnomad ASJ

AF:

0.903

Gnomad EAS

AF:

0.994

Gnomad SAS

AF:

0.834

Gnomad FIN

AF:

0.895

Gnomad MID

AF:

0.867

Gnomad NFE

AF:

0.870

Gnomad OTH

AF:

0.792

GnomAD4 exome

AF:

0.864

AC:

AN:

Hom.:

Cov.:

AF XY:

0.929

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.850

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.744

AC:

113246

AN:

152124

Hom.:

45708

Cov.:

AF XY:

0.750

AC XY:

55797

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.399

AC:

16559

AN:

41456

American (AMR)

AF:

0.851

AC:

13012

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.903

AC:

3132

AN:

3468

East Asian (EAS)

AF:

0.994

AC:

5135

AN:

5166

South Asian (SAS)

AF:

0.835

AC:

4022

AN:

4816

European-Finnish (FIN)

AF:

0.895

AC:

9496

AN:

10606

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.870

AC:

59143

AN:

67998

Other (OTH)

AF:

0.786

AC:

1661

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1117

2234

3350

4467

5584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

822

1644

2466

3288

4110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.829

Hom.:

68269

Bravo

AF:

0.728

Asia WGS

AF:

0.837

AC:

2910

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.7

(source)

DANN

Benign

0.78

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over