rs1064797230

Variant names:

• chr19-5678650-T-C
• rs1064797230
• NM_205767.3:c.260-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_205767.3(MICOS13):​c.260-2A>G variant causes a splice acceptor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.67
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Pathogenic. The variant received 12 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
• PP5: Variant 19-5678650-T-C is Pathogenic according to our data. Variant chr19-5678650-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 425157.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_205767.3. 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
	MICOS13	NM_205767.3	MANE Select	c.260-2A>G		splice_acceptor intron	N/A	NP_991330.1	Q5XKP0
	MICOS13	NM_001308240.2		c.326-2A>G		splice_acceptor intron	N/A	NP_001295169.1	A0A140TA86
	MICOS13	NM_001365761.2		c.326-2A>G		splice_acceptor intron	N/A	NP_001352690.1	A0A140TA86

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICOS13	ENST00000309324.9	TSL:1 MANE Select	c.260-2A>G		splice_acceptor intron	N/A	ENSP00000309561.3	Q5XKP0
	MICOS13	ENST00000587950.5	TSL:2	c.326-2A>G		splice_acceptor intron	N/A	ENSP00000468723.1	A0A140TA86
	MICOS13	ENST00000896351.1		c.287-2A>G		splice_acceptor intron	N/A	ENSP00000566410.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151462 Hom.: 0 Cov.: 32

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

African (AFR) AF: 0.00 AC: 0 AN: 30108

American (AMR) AF: 0.00 AC: 0 AN: 32316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23396

East Asian (EAS) AF: 0.00 AC: 0 AN: 33522

South Asian (SAS) AF: 0.00 AC: 0 AN: 76540

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5516

European-Non Finnish (NFE) AF: 0.0000103 AC: 11 AN: 1062936

Other (OTH) AF: 0.0000354 AC: 2 AN: 56426

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151462 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41260

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67840

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Combined oxidative phosphorylation deficiency 37 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.7
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064797230; hg19: chr19-5678661;