chr21-42893356-G-T

Position:

chr21-42893356-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021075.4(NDUFV3):c.23G>T(p.Arg8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,538,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

NDUFV3
NM_021075.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3211668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NDUFV3	NM_021075.4 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/4	ENST00000354250.7	NP_066553.3
NDUFV3	NM_001001503.2 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/3		NP_001001503.1
NDUFV3	XM_011529586.3 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/5		XP_011527888.1
NDUFV3	XM_017028359.2 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000354250.7 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/4	1	NM_021075.4	ENSP00000346196		P56181-2
NDUFV3	ENST00000340344.4 linkuse as main transcript	c.23G>T	p.Arg8Leu	missense_variant	1/3	1		ENSP00000342895	P1	P56181-1
NDUFV3	ENST00000460740.1 linkuse as main transcript	n.36G>T		non_coding_transcript_exon_variant	1/2	2
NDUFV3	ENST00000460259.1 linkuse as main transcript	n.572-3571G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000149

AC:

AN:

134164

Hom.:

AF XY:

0.0000137

AC XY:

AN XY:

73106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1385980

Hom.:

Cov.:

AF XY:

0.0000453

AC XY:

AN XY:

684002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000658

Gnomad4 OTH exome

AF:

0.0000347

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.23G>T (p.R8L) alteration is located in exon 1 (coding exon 1) of the NDUFV3 gene. This alteration results from a G to T substitution at nucleotide position 23, causing the arginine (R) at amino acid position 8 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.029

.;T

Eigen

Benign

-0.024

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.93

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;N

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0090

D;T

Polyphen

0.98

D;D

Vest4

0.47

MutPred

0.36

Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);

MVP

0.39

MPC

0.36

ClinPred

0.94

GERP RS

2.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.0

Varity_R

0.12

gMVP

0.40

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