Genetic Variant NDUFV3:p.Pro4Leu (chr21-42893344-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021075.4(NDUFV3):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,538,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 1 hom. )

Consequence

NDUFV3
NM_021075.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008732438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV3	NM_021075.4 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 4	ENST00000354250.7	NP_066553.3	P56181-2
NDUFV3	NM_001001503.2 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 3		NP_001001503.1	P56181-1
NDUFV3	XM_011529586.3 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 5		XP_011527888.1
NDUFV3	XM_017028359.2 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFV3	ENST00000354250.7 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 4	1	NM_021075.4	ENSP00000346196.2	P56181-2
NDUFV3	ENST00000340344.4 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 3	1		ENSP00000342895.3	P56181-1
NDUFV3	ENST00000460740.1 link	n.24C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
NDUFV3	ENST00000460259.1 link	n.572-3583C>T		intron_variant	Intron 3 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000231

AC:

AN:

134158

Hom.:

AF XY:

0.000219

AC XY:

AN XY:

73120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000245

Gnomad ASJ exome

AF:

0.00245

Gnomad EAS exome

AF:

0.0000955

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000604

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.0000916

AC:

127

AN:

1386094

Hom.:

Cov.:

AF XY:

0.0000906

AC XY:

AN XY:

684068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00298

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000260

Gnomad4 OTH exome

AF:

0.000243

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000644

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000134

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.66

DANN

Benign

0.82

DEOGEN2

Benign

0.065

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

N;D

REVEL

Benign

0.0090

Sift

Benign

0.20

T;D

Sift4G

Benign

0.20

T;T

Polyphen

0.0040

B;B

Vest4

0.061

MutPred

0.35

Loss of catalytic residue at P4 (P = 0.0036);Loss of catalytic residue at P4 (P = 0.0036);

MVP

0.37

MPC

0.087

ClinPred

0.0080

GERP RS

-0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.042

gMVP

0.14

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over