chr21-42893341-C-A

Position:

• chr21-42893341-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_021075.4(NDUFV3):​c.8C>A​(p.Ala3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,538,246 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. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: NDUFV3 NM_021075.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.120

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050098896).
• BP6: Variant 21-42893341-C-A is Benign according to our data. Variant chr21-42893341-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3045103.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFV3	NM_021075.4	c.8C>A	p.Ala3Asp	missense_variant	1/4	ENST00000354250.7	NP_066553.3
NDUFV3	NM_001001503.2	c.8C>A	p.Ala3Asp	missense_variant	1/3		NP_001001503.1
NDUFV3	XM_011529586.3	c.8C>A	p.Ala3Asp	missense_variant	1/5		XP_011527888.1
NDUFV3	XM_017028359.2	c.8C>A	p.Ala3Asp	missense_variant	1/4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000354250.7	c.8C>A	p.Ala3Asp	missense_variant	1/4	1	NM_021075.4	ENSP00000346196
NDUFV3	ENST00000340344.4	c.8C>A	p.Ala3Asp	missense_variant	1/3	1		ENSP00000342895	P1
NDUFV3	ENST00000460740.1	n.21C>A		non_coding_transcript_exon_variant	1/2	2
NDUFV3	ENST00000460259.1	n.572-3586C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000709 AC: 108 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000470 AC: 63 AN: 134004 Hom.: 1 AF XY: 0.000411 AC XY: 30 AN XY: 73016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.000490

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000801

Gnomad FIN exome AF: 0.00404

Gnomad NFE exome AF: 0.0000605

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000264 AC: 366 AN: 1386012 Hom.: 1 Cov.: 31 AF XY: 0.000241 AC XY: 165 AN XY: 684000

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.000398

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.000784

Gnomad4 FIN exome AF: 0.00520

Gnomad4 NFE exome AF: 0.0000658

Gnomad4 OTH exome AF: 0.000208

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000920 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000357 AC: 8

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NDUFV3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

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	0.32
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.011	.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Benign	0.14
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.53	P;B
Vest4		0.45
MutPred		0.24		Loss of MoRF binding (P = 0.0064);Loss of MoRF binding (P = 0.0064);
MVP		0.46
MPC		0.29
ClinPred		0.13	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.42

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: rs777553859; hg19: chr21-44313451;