chr11-61366177-G-A

Variant names:

• chr11-61366177-G-A
• rs35245221
• NM_016464.5:c.261G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016464.5(TMEM138):​c.261G>A​(p.Val87Val) 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:8
• Conservation: PhyloP100: -0.0440
• 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), G2P, Ambry Genetics, PanelApp Australia
• ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.261G>A	p.Val87Val	synonymous	Exon 3 of 5	NP_057548.1	Q9NPI0-1
	TMEM138	NM_001410999.1		c.261G>A	p.Val87Val	synonymous	Exon 3 of 4	NP_001397928.1	Q9NPI0-3
	TMEM138	NM_001441180.1		c.261G>A	p.Val87Val	synonymous	Exon 3 of 5	NP_001428109.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM138	ENST00000278826.11	TSL:1 MANE Select	c.261G>A	p.Val87Val	synonymous	Exon 3 of 5	ENSP00000278826.5	Q9NPI0-1
	TMEM138	ENST00000542946.2	TSL:1	c.261G>A	p.Val87Val	synonymous	Exon 3 of 3	ENSP00000445792.1	Q9NPI0-2
	TMEM138	ENST00000534963.5	TSL:1	n.360G>A		non_coding_transcript_exon	Exon 4 of 4

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

GnomAD2 exomes AF: 0.00834 AC: 2096 AN: 251440 AF XY: 0.00818

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 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

African (AFR) AF: 0.0589 AC: 1973 AN: 33474

American (AMR) AF: 0.00436 AC: 195 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 147 AN: 26132

East Asian (EAS) AF: 0.00161 AC: 64 AN: 39700

South Asian (SAS) AF: 0.0206 AC: 1774 AN: 86252

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.0404 AC: 233 AN: 5768

European-Non Finnish (NFE) AF: 0.00109 AC: 1215 AN: 1111988

Other (OTH) AF: 0.00937 AC: 566 AN: 60394

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

African (AFR) AF: 0.0563 AC: 2342 AN: 41574

American (AMR) AF: 0.00889 AC: 136 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5194

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68026

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00967 Hom.: 11

Bravo AF: 0.0196

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Joubert syndrome 16 (4)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.6
DANN	Benign	0.63
PhyloP100		-0.044
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35245221; hg19: chr11-61133649;