chr21-42893388-G-A

Position:

• chr21-42893388-G-A

Variant summary

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

The NM_021075.4(NDUFV3):​c.48+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00572 in 1,536,878 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0047 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (34 hom.)
• Consequence: NDUFV3 NM_021075.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002039
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.01

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 (BayesDel_noAF=-0.85).
• BP6: Variant 21-42893388-G-A is Benign according to our data. Variant chr21-42893388-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3055876.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFV3	NM_021075.4	c.48+7G>A		splice_region_variant, intron_variant		ENST00000354250.7	NP_066553.3
NDUFV3	NM_001001503.2	c.48+7G>A		splice_region_variant, intron_variant			NP_001001503.1
NDUFV3	XM_011529586.3	c.48+7G>A		splice_region_variant, intron_variant			XP_011527888.1
NDUFV3	XM_017028359.2	c.48+7G>A		splice_region_variant, intron_variant			XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000354250.7	c.48+7G>A		splice_region_variant, intron_variant		1	NM_021075.4	ENSP00000346196
NDUFV3	ENST00000340344.4	c.48+7G>A		splice_region_variant, intron_variant		1		ENSP00000342895	P1
NDUFV3	ENST00000460259.1	n.572-3539G>A		intron_variant, non_coding_transcript_variant		2
NDUFV3	ENST00000460740.1	n.61+7G>A		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 709 AN: 152234 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00590 AC: 787 AN: 133414 Hom.: 5 AF XY: 0.00559 AC XY: 407 AN XY: 72852

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.00985

Gnomad ASJ exome AF: 0.00918

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00217

Gnomad FIN exome AF: 0.000956

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00583 AC: 8073 AN: 1384528 Hom.: 34 Cov.: 31 AF XY: 0.00585 AC XY: 3999 AN XY: 683326

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00992

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.000945

Gnomad4 NFE exome AF: 0.00617

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152350 Hom.: 4 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74512

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00628

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00640 Hom.: 0

Bravo AF: 0.00544

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

Dec 30, 2021

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
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.028
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: rs141846205; hg19: chr21-44313498;