rs141922962

chr21-42897046-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_021075.4(NDUFV3):c.168A>C(p.Lys56Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,613,980 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (34 hom.)
• Consequence: NDUFV3 NM_021075.4 missense, splice_region
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.48

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 -6 ACMG points.

• BP6: Variant 21-42897046-A-C is Benign according to our data. Variant chr21-42897046-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 403223.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42897046-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFV3	NM_021075.4	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/4	ENST00000354250.7
NDUFV3	NM_001001503.2	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/3
NDUFV3	XM_011529586.3	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/5
NDUFV3	XM_017028359.2	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFV3	ENST00000354250.7	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/4	1	NM_021075.4
NDUFV3	ENST00000340344.4	c.168A>C	p.Lys56Asn	missense_variant, splice_region_variant	2/3	1		P1
NDUFV3	ENST00000460259.1	n.691A>C		splice_region_variant, non_coding_transcript_exon_variant	4/6	2
NDUFV3	ENST00000460740.1	n.61+3665A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 152180 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00548 AC: 1377 AN: 251260 Hom.: 7 AF XY: 0.00543 AC XY: 738 AN XY: 135828

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00983

Gnomad ASJ exome AF: 0.00874

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00679

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00577 AC: 8434 AN: 1461682 Hom.: 34 Cov.: 31 AF XY: 0.00579 AC XY: 4212 AN XY: 727138

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00617

Gnomad4 OTH exome AF: 0.00772

GnomAD4 genome AF: 0.00466 AC: 709 AN: 152298 Hom.: 3 Cov.: 31 AF XY: 0.00446 AC XY: 332 AN XY: 74462

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00818

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00625

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00684 Hom.: 8

Bravo AF: 0.00544

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00502 AC: 610

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00806

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene not associated to pt disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.71	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.069
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		1.0	D;D
Vest4		0.48
MutPred		0.35		Loss of methylation at K56 (P = 7e-04);Loss of methylation at K56 (P = 7e-04);
MVP		0.54
MPC		0.49
ClinPred		0.023	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141922962; hg19: chr21-44317156;