19-5678650-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate

The NM_205767.3(MICOS13):​c.260-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000987 in 1,519,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MICOS13
NM_205767.3 splice_acceptor

Scores

1
3
3
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.67
Variant links:
Genes affected
MICOS13 (HGNC:33702): (mitochondrial contact site and cristae organizing system subunit 13) Involved in cristae formation. Located in mitochondrial crista junction and nucleoplasm. Part of MICOS complex. Implicated in combined oxidative phosphorylation deficiency 37. [provided by Alliance of Genome Resources, Apr 2022]
RPL36 (HGNC:13631): (ribosomal protein L36) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 19-5678650-T-C is Pathogenic according to our data. Variant chr19-5678650-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 425157.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MICOS13NM_205767.3 linkuse as main transcriptc.260-2A>G splice_acceptor_variant ENST00000309324.9
MICOS13NM_001308240.2 linkuse as main transcriptc.326-2A>G splice_acceptor_variant
MICOS13NM_001365761.2 linkuse as main transcriptc.326-2A>G splice_acceptor_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MICOS13ENST00000309324.9 linkuse as main transcriptc.260-2A>G splice_acceptor_variant 1 NM_205767.3 P1
MICOS13ENST00000587950.5 linkuse as main transcriptc.326-2A>G splice_acceptor_variant 2
RPL36ENST00000579649.5 linkuse as main transcriptc.-60+3678T>C intron_variant 5 P1
MICOS13ENST00000585605.1 linkuse as main transcriptn.359-2A>G splice_acceptor_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000660
AC:
1
AN:
151462
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000102
AC:
14
AN:
1367886
Hom.:
0
Cov.:
31
AF XY:
0.00000891
AC XY:
6
AN XY:
673616
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000212
Gnomad4 NFE exome
AF:
0.0000103
Gnomad4 OTH exome
AF:
0.0000354
GnomAD4 genome
AF:
0.00000660
AC:
1
AN:
151462
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
73992
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 37 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 22, 2019- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
0.0020
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
26
DANN
Uncertain
0.98
Eigen
Pathogenic
0.79
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.92
D
MutationTaster
Benign
1.0
D;D;D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.74
Position offset: -46
DS_AL_spliceai
0.99
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064797230; hg19: chr19-5678661; API