21-42893343-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_021075.4(NDUFV3):c.10C>T(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,538,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NDUFV3 NM_021075.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037558377).
• BP6: Variant 21-42893343-C-T is Benign according to our data. Variant chr21-42893343-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3034982.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFV3	NM_021075.4	c.10C>T	p.Pro4Ser	missense_variant	1/4	ENST00000354250.7
NDUFV3	NM_001001503.2	c.10C>T	p.Pro4Ser	missense_variant	1/3
NDUFV3	XM_011529586.3	c.10C>T	p.Pro4Ser	missense_variant	1/5
NDUFV3	XM_017028359.2	c.10C>T	p.Pro4Ser	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFV3	ENST00000354250.7	c.10C>T	p.Pro4Ser	missense_variant	1/4	1	NM_021075.4
NDUFV3	ENST00000340344.4	c.10C>T	p.Pro4Ser	missense_variant	1/3	1		P1
NDUFV3	ENST00000460740.1	n.23C>T		non_coding_transcript_exon_variant	1/2	2
NDUFV3	ENST00000460259.1	n.572-3584C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000231 AC: 31 AN: 134272 Hom.: 0 AF XY: 0.000178 AC XY: 13 AN XY: 73152

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.000409

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 147 AN: 1386148 Hom.: 0 Cov.: 31 AF XY: 0.0000804 AC XY: 55 AN XY: 684076

Gnomad4 AFR exome AF: 0.00362

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000742

Gnomad4 OTH exome AF: 0.000139

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74504

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.00124

ExAC AF: 0.000267 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NDUFV3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 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	0.056
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.0040
Dann	Benign	0.72
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.021
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.041
MutPred		0.22		Loss of catalytic residue at P4 (P = 0.0134);Loss of catalytic residue at P4 (P = 0.0134);
MVP		0.30
MPC		0.086
ClinPred		0.0092	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.085

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

Other links and lift over

dbSNP: rs573166856; hg19: chr21-44313453;