21-42903351-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_021075.4(NDUFV3):c.339G>A(p.Pro113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0729 in 1,614,102 control chromosomes in the GnomAD database, including 5,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.065 (418 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4595 hom.)
• Consequence: NDUFV3 NM_021075.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.597

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-42903351-G-A is Benign according to our data. Variant chr21-42903351-G-A is described in ClinVar as [Benign]. Clinvar id is 3056561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.597 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFV3	NM_021075.4	c.339G>A	p.Pro113=	synonymous_variant	3/4	ENST00000354250.7
NDUFV3	XM_011529586.3	c.339G>A	p.Pro113=	synonymous_variant	3/5
NDUFV3	NM_001001503.2	c.170-5513G>A		intron_variant
NDUFV3	XM_017028359.2	c.170-3489G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFV3	ENST00000354250.7	c.339G>A	p.Pro113=	synonymous_variant	3/4	1	NM_021075.4
NDUFV3	ENST00000340344.4	c.170-5513G>A		intron_variant		1		P1
NDUFV3	ENST00000460259.1	n.862G>A		non_coding_transcript_exon_variant	5/6	2
NDUFV3	ENST00000460740.1	n.231G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9928 AN: 152100 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.0488

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0608

GnomAD3 exomes AF: 0.0820 AC: 20610 AN: 251490 Hom.: 1002 AF XY: 0.0853 AC XY: 11599 AN XY: 135922

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.0888

Gnomad ASJ exome AF: 0.0665

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0737 AC: 107699 AN: 1461884 Hom.: 4595 Cov.: 31 AF XY: 0.0763 AC XY: 55522 AN XY: 727244

Gnomad4 AFR exome AF: 0.0467

Gnomad4 AMR exome AF: 0.0880

Gnomad4 ASJ exome AF: 0.0671

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0675

Gnomad4 OTH exome AF: 0.0733

GnomAD4 genome AF: 0.0653 AC: 9943 AN: 152218 Hom.: 418 Cov.: 32 AF XY: 0.0669 AC XY: 4978 AN XY: 74424

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.0778

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0349

Gnomad4 NFE AF: 0.0647

Gnomad4 OTH AF: 0.0602

Alfa AF: 0.0693 Hom.: 618

Bravo AF: 0.0682

Asia WGS AF: 0.132 AC: 460 AN: 3478

EpiCase AF: 0.0658

EpiControl AF: 0.0674

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NDUFV3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2019

This variant is classified as 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
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.0
Dann	Benign	0.41

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: rs4148972; hg19: chr21-44323461;