chr19-29208159-C-G

Position:

• chr19-29208159-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PM2 PP3_Strong PP5_Moderate

The NM_006003.3(UQCRFS1):​c.215-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: UQCRFS1 NM_006003.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.80

Genes affected

UQCRFS1 (HGNC:12587): (ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1) Predicted to enable oxidoreductase activity. Involved in mitochondrial respiratory chain complex III assembly and respiratory electron transport chain. Located in mitochondrion. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. Implicated in mitochondrial complex III deficiency. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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 19-29208159-C-G is Pathogenic according to our data. Variant chr19-29208159-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 619297.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-29208159-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UQCRFS1	NM_006003.3	c.215-1G>C		splice_acceptor_variant		ENST00000304863.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UQCRFS1	ENST00000304863.6	c.215-1G>C		splice_acceptor_variant		1	NM_006003.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex 3 deficiency, nuclear type 10 Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Jul 12, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2020	- -

Lactic acidosis;C0268579:Propionic acidemia;C0878544:Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Feb 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -31
DS_AL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1568344751; hg19: chr19-29699066;