chr21-42893344-C-G

Position:

• chr21-42893344-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_021075.4(NDUFV3):​c.11C>G​(p.Pro4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,538,452 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: NDUFV3 NM_021075.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.215

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040231645).
• BP6: Variant 21-42893344-C-G is Benign according to our data. Variant chr21-42893344-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 781907.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFV3	NM_021075.4	c.11C>G	p.Pro4Arg	missense_variant	1/4	ENST00000354250.7	NP_066553.3
NDUFV3	NM_001001503.2	c.11C>G	p.Pro4Arg	missense_variant	1/3		NP_001001503.1
NDUFV3	XM_011529586.3	c.11C>G	p.Pro4Arg	missense_variant	1/5		XP_011527888.1
NDUFV3	XM_017028359.2	c.11C>G	p.Pro4Arg	missense_variant	1/4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000354250.7	c.11C>G	p.Pro4Arg	missense_variant	1/4	1	NM_021075.4	ENSP00000346196
NDUFV3	ENST00000340344.4	c.11C>G	p.Pro4Arg	missense_variant	1/3	1		ENSP00000342895	P1
NDUFV3	ENST00000460740.1	n.24C>G		non_coding_transcript_exon_variant	1/2	2
NDUFV3	ENST00000460259.1	n.572-3583C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00167 AC: 224 AN: 134158 Hom.: 0 AF XY: 0.00197 AC XY: 144 AN XY: 73120

Gnomad AFR exome AF: 0.000301

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00196

Gnomad EAS exome AF: 0.000191

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.000245

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00184 AC: 2557 AN: 1386092 Hom.: 2 Cov.: 31 AF XY: 0.00193 AC XY: 1321 AN XY: 684066

Gnomad4 AFR exome AF: 0.000222

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00163

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.000388

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74510

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.00151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000771 AC: 4

ExAC AF: 0.00170 AC: 38

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2023	- -

NDUFV3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 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	0.083
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.46
DANN	Benign	0.72
DEOGEN2	Benign	0.016	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.014
Sift	Benign	0.61	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.019	B;B
Vest4		0.066
MVP		0.45
MPC		0.092
ClinPred		0.00034	T
GERP RS		-0.21
Varity_R		0.050
gMVP		0.12

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: rs77606940; hg19: chr21-44313454;