21-42893360-A-T

Position:

chr21-42893360-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021075.4(NDUFV3):c.27A>T(p.Gln9His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000975 in 1,538,120 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

NDUFV3
NM_021075.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

Variant links:

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]

NDUFV3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16017115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFV3	NM_021075.4 link	c.27A>T	p.Gln9His	missense_variant	1/4	ENST00000354250.7	NP_066553.3	P56181-2
NDUFV3	NM_001001503.2 link	c.27A>T	p.Gln9His	missense_variant	1/3		NP_001001503.1	P56181-1
NDUFV3	XM_011529586.3 link	c.27A>T	p.Gln9His	missense_variant	1/5		XP_011527888.1
NDUFV3	XM_017028359.2 link	c.27A>T	p.Gln9His	missense_variant	1/4		XP_016883848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NDUFV3	ENST00000354250.7 link	c.27A>T	p.Gln9His	missense_variant	1/4	1	NM_021075.4	ENSP00000346196.2	P56181-2
NDUFV3	ENST00000340344.4 link	c.27A>T	p.Gln9His	missense_variant	1/3	1		ENSP00000342895.3	P56181-1
NDUFV3	ENST00000460740.1 link	n.40A>T		non_coding_transcript_exon_variant	1/2	2
NDUFV3	ENST00000460259.1 link	n.572-3567A>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000149

AC:

AN:

134050

Hom.:

AF XY:

0.0000137

AC XY:

AN XY:

73104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000402

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000794

AC:

AN:

1385906

Hom.:

Cov.:

AF XY:

0.0000102

AC XY:

AN XY:

683960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000360

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

The c.27A>T (p.Q9H) alteration is located in exon 1 (coding exon 1) of the NDUFV3 gene. This alteration results from a A to T substitution at nucleotide position 27, causing the glutamine (Q) at amino acid position 9 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0094

.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.95

N;N

REVEL

Benign

0.060

Sift

Benign

0.13

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.99

D;P

Vest4

0.24

MutPred

0.17

Loss of disorder (P = 0.0518);Loss of disorder (P = 0.0518);

MVP

0.46

MPC

0.40

ClinPred

0.59

GERP RS

-0.038

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Varity_R

0.11

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over