Genetic Variant UQCRC1:p.Asn301Ser (chr3-48601039-T-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003365.3(UQCRC1):c.902A>G(p.Asn301Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,610,450 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 7 hom. )

Consequence

UQCRC1
NM_003365.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.76

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01315853).

BP6

Variant 3-48601039-T-C is Benign according to our data. Variant chr3-48601039-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3042768.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 372 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UQCRC1	NM_003365.3 link	c.902A>G	p.Asn301Ser	missense_variant	Exon 8 of 13	ENST00000203407.6	NP_003356.2	P31930

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UQCRC1	ENST00000203407.6 link	c.902A>G	p.Asn301Ser	missense_variant	Exon 8 of 13	1	NM_003365.3	ENSP00000203407.5		P31930

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

372

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00459

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00234

AC:

586

AN:

250602

Hom.:

AF XY:

0.00227

AC XY:

308

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00427

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00338

AC:

4922

AN:

1458114

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

2376

AN XY:

724426

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.000963

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.00133

Gnomad4 NFE exome

AF:

0.00414

Gnomad4 OTH exome

AF:

0.00263

GnomAD4 genome

AF:

0.00244

AC:

372

AN:

152336

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

159

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00459

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00380

Hom.:

Bravo

AF:

0.00237

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00228

AC:

277

EpiCase

AF:

0.00502

EpiControl

AF:

0.00557

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

UQCRC1-related disorder

Benign:1

Feb 04, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.073

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0096

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

REVEL

Benign

0.13

Sift

Benign

0.43

Sift4G

Benign

0.41

Polyphen

1.0

Vest4

0.59

MVP

0.16

MPC

0.55

ClinPred

0.026

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over