19-5679715-G-T

Variant names:

• chr19-5679715-G-T
• NM_205767.3:c.78C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_205767.3(MICOS13):​c.78C>A​(p.Tyr26*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MICOS13 NM_205767.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.24

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.782 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-5679715-G-T is Pathogenic according to our data. Variant chr19-5679715-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3126314.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICOS13	NM_205767.3	c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	ENST00000309324.9	NP_991330.1
MICOS13	NM_001308240.2	c.144C>A	p.Tyr48*	stop_gained	Exon 3 of 5		NP_001295169.1
MICOS13	NM_001365761.2	c.144C>A	p.Tyr48*	stop_gained	Exon 2 of 4		NP_001352690.1
MICOS13	XM_011527675.3	c.144C>A	p.Tyr48*	stop_gained	Exon 2 of 4		XP_011525977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICOS13	ENST00000309324.9	c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	1	NM_205767.3	ENSP00000309561.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Aug 27, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.78C>A (p.Y26*) alteration, located in exon 2 (coding exon 2) of the C19orf70 gene, consists of a C to A substitution at nucleotide position 78. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 26. The predicted stop codon occurs in the 5' end of the C19orf70 gene. Premature termination codons in the 5&rsquo; end of a gene have been reported to escape nonsense-mediated mRNA decay and/or lead to re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). Direct evidence for this alteration is unavailable; however, premature termination codons are typically deleterious in nature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.47	N
Vest4		0.38
GERP RS		-6.8

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-5679726;