rs141922962

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_021075.4(NDUFV3):c.168A>C(p.Lys56Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,613,980 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0058 ( 34 hom. )

Consequence

NDUFV3
NM_021075.4 missense, splice_region

Scores

Splicing: ADA: 0.9955

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.48

Publications

12 publications found

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 was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 21-42897046-A-C is Benign according to our data. Variant chr21-42897046-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 403223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV3	NM_021075.4 link	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000354250.7	NP_066553.3	P56181-2
NDUFV3	NM_001001503.2 link	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	Exon 2 of 3		NP_001001503.1	P56181-1
NDUFV3	XM_011529586.3 link	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	Exon 2 of 5		XP_011527888.1
NDUFV3	XM_017028359.2 link	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	Exon 2 of 4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFV3	ENST00000354250.7 link	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_021075.4	ENSP00000346196.2	P56181-2
NDUFV3	ENST00000340344.4 link	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	Exon 2 of 3	1		ENSP00000342895.3	P56181-1
NDUFV3	ENST00000460259.1 link	n.691A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6	2
NDUFV3	ENST00000460740.1 link	n.61+3665A>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

707

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00548

AC:

1377

AN:

251260

AF XY:

0.00543

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00983

Gnomad ASJ exome

AF:

0.00874

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00679

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.00577

AC:

8434

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

4212

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

33476

American (AMR)

AF:

0.00977

AC:

437

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0100

AC:

262

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00217

AC:

187

AN:

86244

European-Finnish (FIN)

AF:

0.000880

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.0158

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00617

AC:

6863

AN:

1111876

Other (OTH)

AF:

0.00772

AC:

466

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

427

854

1282

1709

2136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00466

AC:

709

AN:

152298

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

332

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41576

American (AMR)

AF:

0.00818

AC:

125

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00625

AC:

425

AN:

68016

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00629

Hom.:

Bravo

AF:

0.00544

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00502

AC:

610

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00806

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NDUFV3: BP4, BS2 -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene not associated to pt disease. -

NDUFV3-related disorder

Benign:1

Jul 18, 2024

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

Uncertain

0.35

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

L;L

PhyloP100

1.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.069

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.042

D;D

Polyphen

1.0

D;D

Vest4

0.48

MutPred

0.35

Loss of methylation at K56 (P = 7e-04);Loss of methylation at K56 (P = 7e-04);

MVP

0.54

MPC

0.49

ClinPred

0.023

GERP RS

2.4

Varity_R

0.12

gMVP

0.31

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: 1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over