11-61362321-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000542946.2(TMEM138):c.-239C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 152,332 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM138 ENST00000542946.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.00800

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]

CYB561A3 (HGNC:23014): (cytochrome b561 family member A3) Predicted to enable transmembrane ascorbate ferrireductase activity. Predicted to be involved in cellular iron ion homeostasis. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-61362321-C-T is Benign according to our data. Variant chr11-61362321-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305054.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0135 (2057/152332) while in subpopulation NFE AF= 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 22 homozygotes in gnomad4. There are 918 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB561A3	NM_001161454.1			upstream_gene_variant
CYB561A3	XM_011544821.3			upstream_gene_variant
CYB561A3	XM_024448398.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM138	ENST00000542946.2	c.-239C>T		5_prime_UTR_variant	1/3	1
TMEM138	ENST00000451389.7	c.-239C>T		5_prime_UTR_variant	1/5	3
TMEM138	ENST00000685597.1	c.-239C>T		5_prime_UTR_variant	1/5

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2059 AN: 152214 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00487

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.00907

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 46 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 28

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0135 AC: 2057 AN: 152332 Hom.: 22 Cov.: 33 AF XY: 0.0123 AC XY: 918 AN XY: 74482

Gnomad4 AFR AF: 0.00486

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0143 Hom.: 3

Bravo AF: 0.0129

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	6.6
Dann	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs146156958; hg19: chr11-61129793;