chr21-42897046-A-C

Position:

chr21-42897046-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_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:3

Conservation

PhyloP100: 1.48

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 -12 ACMG points.

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 id is 403223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42897046-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NDUFV3	NM_021075.4 linkuse as main transcript	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/4	ENST00000354250.7	NP_066553.3
NDUFV3	NM_001001503.2 linkuse as main transcript	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/3		NP_001001503.1
NDUFV3	XM_011529586.3 linkuse as main transcript	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/5		XP_011527888.1
NDUFV3	XM_017028359.2 linkuse as main transcript	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000354250.7 linkuse as main transcript	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/4	1	NM_021075.4	ENSP00000346196		P56181-2
NDUFV3	ENST00000340344.4 linkuse as main transcript	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/3	1		ENSP00000342895	P1	P56181-1
NDUFV3	ENST00000460259.1 linkuse as main transcript	n.691A>C		splice_region_variant, non_coding_transcript_exon_variant	4/6	2
NDUFV3	ENST00000460740.1 linkuse as main transcript	n.61+3665A>C		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes

AF:

0.00548

AC:

1377

AN:

251260

Hom.:

AF XY:

0.00543

AC XY:

738

AN XY:

135828

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 SAS exome

AF:

0.00209

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

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00977

Gnomad4 ASJ exome

AF:

0.0100

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00217

Gnomad4 FIN exome

AF:

0.000880

Gnomad4 NFE exome

AF:

0.00617

Gnomad4 OTH exome

AF:

0.00772

GnomAD4 genome

AF:

0.00466

AC:

709

AN:

152298

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

332

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00818

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00625

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.00684

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

0.71

N;N

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

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

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