Genetic Variant NM_003365.3:c.1133G>C (chr3-48600562-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003365.3(UQCRC1):c.1133G>C(p.Arg378Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R378H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

UQCRC1
NM_003365.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81

Publications

2 publications found

Variant links:

Genes affected

UQCRC1 (HGNC:12585): (ubiquinol-cytochrome c reductase core protein 1) Enables ubiquitin protein ligase binding activity. Predicted to be involved in oxidative phosphorylation. Predicted to act upstream of or within mitochondrial electron transport, ubiquinol to cytochrome c. Located in mitochondrion. Implicated in Alzheimer's disease. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

UQCRC1 Gene-Disease associations (from GenCC):

parkinsonism with polyneuropathy
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

UQCRC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003365.3. 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
	UQCRC1	NM_003365.3	MANE Select	c.1133G>C	p.Arg378Pro	missense	Exon 10 of 13	NP_003356.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UQCRC1	ENST00000203407.6	TSL:1 MANE Select	c.1133G>C	p.Arg378Pro	missense	Exon 10 of 13	ENSP00000203407.5	P31930
UQCRC1	ENST00000899333.1		c.1178G>C	p.Arg393Pro	missense	Exon 10 of 13	ENSP00000569392.1
UQCRC1	ENST00000912156.1		c.1124G>C	p.Arg375Pro	missense	Exon 10 of 13	ENSP00000582215.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

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

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

3.5

PhyloP100

3.8

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.71

MutPred

0.66

Loss of catalytic residue at R378 (P = 0.0125)

MVP

0.48

MPC

1.0

ClinPred

0.99

GERP RS

5.8

Varity_R

0.99

gMVP

0.90

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over