rs10595

Variant names:

• chr21-42904255-G-A
• rs10595
• NM_021075.4:c.1243G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021075.4(NDUFV3):​c.1243G>A​(p.Asp415Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,604,424 control chromosomes in the GnomAD database, including 290,981 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (28444 hom., cov: 32)
  • Exomes 𝑓: 0.60 (262537 hom.)
• Consequence: NDUFV3 NM_021075.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.773
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4735414E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFV3	NM_021075.4	c.1243G>A	p.Asp415Asn	missense_variant	Exon 3 of 4	ENST00000354250.7	NP_066553.3
NDUFV3	XM_011529586.3	c.1243G>A	p.Asp415Asn	missense_variant	Exon 3 of 5		XP_011527888.1
NDUFV3	NM_001001503.2	c.170-4609G>A		intron_variant	Intron 2 of 2		NP_001001503.1
NDUFV3	XM_017028359.2	c.170-2585G>A		intron_variant	Intron 2 of 3		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000354250.7	c.1243G>A	p.Asp415Asn	missense_variant	Exon 3 of 4	1	NM_021075.4	ENSP00000346196.2
NDUFV3	ENST00000340344.4	c.170-4609G>A		intron_variant	Intron 2 of 2	1		ENSP00000342895.3
NDUFV3	ENST00000460259.1	n.1766G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.603 AC: 91662 AN: 151928 Hom.: 28411 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.549 AC: 126731 AN: 230690 AF XY: 0.556

Gnomad AFR exome AF: 0.718

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.577

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.607

Gnomad OTH exome AF: 0.538

GnomAD4 exome AF: 0.597 AC: 867304 AN: 1452378 Hom.: 262537 Cov.: 73 AF XY: 0.597 AC XY: 430611 AN XY: 721614

African (AFR) AF: 0.716 AC: 23866 AN: 33328

American (AMR) AF: 0.345 AC: 14777 AN: 42776

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14770 AN: 25946

East Asian (EAS) AF: 0.365 AC: 14371 AN: 39346

South Asian (SAS) AF: 0.570 AC: 48524 AN: 85094

European-Finnish (FIN) AF: 0.627 AC: 33051 AN: 52746

Middle Eastern (MID) AF: 0.547 AC: 3118 AN: 5698

European-Non Finnish (NFE) AF: 0.614 AC: 680392 AN: 1107370

Other (OTH) AF: 0.573 AC: 34435 AN: 60074

GnomAD4 genome AF: 0.603 AC: 91739 AN: 152046 Hom.: 28444 Cov.: 32 AF XY: 0.600 AC XY: 44604 AN XY: 74302

African (AFR) AF: 0.711 AC: 29515 AN: 41492

American (AMR) AF: 0.427 AC: 6513 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1980 AN: 3472

East Asian (EAS) AF: 0.339 AC: 1752 AN: 5172

South Asian (SAS) AF: 0.555 AC: 2675 AN: 4818

European-Finnish (FIN) AF: 0.629 AC: 6635 AN: 10550

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.600 AC: 40773 AN: 67970

Other (OTH) AF: 0.553 AC: 1171 AN: 2116

Alfa AF: 0.595 Hom.: 134520

Bravo AF: 0.589

TwinsUK AF: 0.615 AC: 2282

ALSPAC AF: 0.626 AC: 2413

ESP6500AA AF: 0.705 AC: 3106

ESP6500EA AF: 0.609 AC: 5240

ExAC AF: 0.550 AC: 66620

Asia WGS AF: 0.439 AC: 1531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Benign	0.97
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.77
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.083
Sift	Uncertain	0.021	D
Sift4G	Benign	0.12	T
Vest4		0.026
MPC		0.12
ClinPred		0.0070	T
GERP RS		2.9
gMVP		0.074
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10595; hg19: chr21-44324365; COSMIC: COSV61086981; COSMIC: COSV61086981;