3-48600977-C-T

Variant names:

• chr3-48600977-C-T
• rs555118861
• NM_003365.3:c.964G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003365.3(UQCRC1):​c.964G>A​(p.Val322Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,603,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: UQCRC1 NM_003365.3 missense, splice_region
• Scores: Splicing: ADA: 0.00005367
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029720873).
• BS2: High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UQCRC1	NM_003365.3	c.964G>A	p.Val322Met	missense_variant, splice_region_variant	Exon 8 of 13	ENST00000203407.6	NP_003356.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UQCRC1	ENST00000203407.6	c.964G>A	p.Val322Met	missense_variant, splice_region_variant	Exon 8 of 13	1	NM_003365.3	ENSP00000203407.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 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: 0.000386

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

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 247582 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 133826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1450944 Hom.: 0 Cov.: 32 AF XY: 0.0000195 AC XY: 14 AN XY: 719522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74508

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinsonism with polyneuropathy Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.964G>A (p.Val322Met) in the UQCRC1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and novel (not in any individuals) in 1000 Genomes. The amino acid Valine at position 322 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val322Met in UQCRC1 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.6
DANN	Benign	0.97
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.031
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.0060	B
Vest4		0.28
MutPred		0.30		Loss of catalytic residue at V322 (P = 0.0059);
MVP		0.11
MPC		0.22
ClinPred		0.056	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.065
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.21
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: rs555118861; hg19: chr3-48638410;