19-5678601-G-A

Variant names:

• chr19-5678601-G-A
• rs200518759
• NM_205767.3:c.307C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_205767.3(MICOS13):​c.307C>T​(p.Arg103Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000582 in 1,547,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: MICOS13 NM_205767.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047701).

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.307C>T	p.Arg103Cys	missense	Exon 4 of 4	NP_991330.1	Q5XKP0
	MICOS13	NM_001308240.2		c.373C>T	p.Arg125Cys	missense	Exon 5 of 5	NP_001295169.1	A0A140TA86
	MICOS13	NM_001365761.2		c.373C>T	p.Arg125Cys	missense	Exon 4 of 4	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.307C>T	p.Arg103Cys	missense	Exon 4 of 4	ENSP00000309561.3	Q5XKP0
	MICOS13	ENST00000587950.5	TSL:2	c.373C>T	p.Arg125Cys	missense	Exon 4 of 4	ENSP00000468723.1	A0A140TA86
	MICOS13	ENST00000896351.1		c.334C>T	p.Arg112Cys	missense	Exon 4 of 4	ENSP00000566410.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000661 AC: 1 AN: 151290 AF XY: 0.0000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000573 AC: 8 AN: 1395404 Hom.: 0 Cov.: 31 AF XY: 0.00000581 AC XY: 4 AN XY: 688336

African (AFR) AF: 0.00 AC: 0 AN: 31412

American (AMR) AF: 0.00 AC: 0 AN: 35104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 35566

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00000557 AC: 6 AN: 1077754

Other (OTH) AF: 0.00 AC: 0 AN: 57846

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.2
DANN	Benign	0.95
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.0
PROVEAN	Benign	2.0	N
REVEL	Benign	0.024
Sift	Benign	0.23	T
Sift4G	Benign	0.15	T
Vest4		0.13
MutPred		0.26		Loss of MoRF binding (P = 0.0028)
MVP		0.040
MPC		0.12
ClinPred		0.064	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs200518759; hg19: chr19-5678612;