chr11-61362081-A-C

Position:

• chr11-61362081-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The ENST00000542946.2(TMEM138):​c.-479A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 152,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM138 ENST00000542946.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.95

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00286 (436/152294) while in subpopulation SAS AF= 0.00579 (28/4834). AF 95% confidence interval is 0.00412. There are 0 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB561A3	NM_001161454.1	c.-578T>G		5_prime_UTR_variant	1/8		NP_001154926.1
CYB561A3	XM_011544821.3	c.-578T>G		5_prime_UTR_variant	1/8		XP_011543123.1
CYB561A3	XM_024448398.2	c.-578T>G		5_prime_UTR_variant	1/7		XP_024304166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM138	ENST00000542946.2	c.-479A>C		5_prime_UTR_variant	1/3	1		ENSP00000445792
CYB561A3	ENST00000426130.6	c.-578T>G		5_prime_UTR_variant	1/8	5		ENSP00000398979
CYB561A3	ENST00000537680.5	c.-273T>G		5_prime_UTR_variant	1/4	4		ENSP00000439702

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00599

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.00383

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 120 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84

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: 0.00286 AC: 436 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74480

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00579

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00423

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00344 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.042
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs192845534; hg19: chr11-61129553;