21-42893344-C-G

Position:

chr21-42893344-C-G

Variant summary

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

The NM_021075.4(NDUFV3):c.11C>G(p.Pro4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,538,452 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 2 hom. )

Consequence

NDUFV3
NM_021075.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.215

Variant links:

Genes affected

NDUFV3 (HGNC:7719): (NADH:ubiquinone oxidoreductase subunit V3) The protein encoded by this gene is one of at least forty-one subunits that make up the NADH-ubiquinone oxidoreductase complex. This complex is part of the mitochondrial respiratory chain and serves to catalyze the rotenone-sensitive oxidation of NADH and the reduction of ubiquinone. The encoded protein is one of three proteins found in the flavoprotein fraction of the complex. The specific function of the encoded protein is unknown. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NDUFV3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040231645).

BP6

Variant 21-42893344-C-G is Benign according to our data. Variant chr21-42893344-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 781907.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NDUFV3	NM_021075.4 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/4	ENST00000354250.7
NDUFV3	NM_001001503.2 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/3
NDUFV3	XM_011529586.3 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/5
NDUFV3	XM_017028359.2 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFV3	ENST00000354250.7 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/4	1	NM_021075.4		P56181-2
NDUFV3	ENST00000340344.4 linkuse as main transcript	c.11C>G	p.Pro4Arg	missense_variant	1/3	1		P1	P56181-1
NDUFV3	ENST00000460740.1 linkuse as main transcript	n.24C>G		non_coding_transcript_exon_variant	1/2	2
NDUFV3	ENST00000460259.1 linkuse as main transcript	n.572-3583C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00167

AC:

224

AN:

134158

Hom.:

AF XY:

0.00197

AC XY:

144

AN XY:

73120

show subpopulations

Gnomad AFR exome

AF:

0.000301

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00196

Gnomad EAS exome

AF:

0.000191

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.000245

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00184

AC:

2557

AN:

1386092

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1321

AN XY:

684066

show subpopulations

Gnomad4 AFR exome

AF:

0.000222

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00163

Gnomad4 EAS exome

AF:

0.0000560

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.000388

Gnomad4 NFE exome

AF:

0.00200

Gnomad4 OTH exome

AF:

0.00185

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152360

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00372

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00204

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000771

AC:

ExAC

AF:

0.00170

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2023	- -

NDUFV3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

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

0.083

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.46

DANN

Benign

0.72

DEOGEN2

Benign

0.016

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.40

T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.014

Sift

Benign

0.61

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.019

B;B

Vest4

0.066

MVP

0.45

MPC

0.092

ClinPred

0.00034

GERP RS

-0.21

Varity_R

0.050

gMVP

0.12

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