chr19-29213078-A-T

Position:

• chr19-29213078-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_006003.3(UQCRFS1):​c.41T>A​(p.Val14Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: UQCRFS1 NM_006003.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.61

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-29213078-A-T is Pathogenic according to our data. Variant chr19-29213078-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 619501.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-29213078-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UQCRFS1	NM_006003.3	c.41T>A	p.Val14Asp	missense_variant	1/2	ENST00000304863.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UQCRFS1	ENST00000304863.6	c.41T>A	p.Val14Asp	missense_variant	1/2	1	NM_006003.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex 3 deficiency, nuclear type 10 Pathogenic:1

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
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.083	T
Polyphen		0.75	P
Vest4		0.30
MutPred		0.69		Loss of helix (P = 0.0376);
MVP		0.63
MPC		2.1
ClinPred		0.77	D
GERP RS		4.2
Varity_R		0.82
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs1568346416; hg19: chr19-29703985;