chr21-42903486-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021075.4(NDUFV3):​c.474C>A​(p.Ser158Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

NDUFV3
NM_021075.4 missense

Scores

8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NDUFV3NM_021075.4 linkuse as main transcriptc.474C>A p.Ser158Arg missense_variant 3/4 ENST00000354250.7 NP_066553.3
NDUFV3XM_011529586.3 linkuse as main transcriptc.474C>A p.Ser158Arg missense_variant 3/5 XP_011527888.1
NDUFV3NM_001001503.2 linkuse as main transcriptc.170-5378C>A intron_variant NP_001001503.1
NDUFV3XM_017028359.2 linkuse as main transcriptc.170-3354C>A intron_variant XP_016883848.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NDUFV3ENST00000354250.7 linkuse as main transcriptc.474C>A p.Ser158Arg missense_variant 3/41 NM_021075.4 ENSP00000346196 P56181-2
NDUFV3ENST00000340344.4 linkuse as main transcriptc.170-5378C>A intron_variant 1 ENSP00000342895 P1P56181-1
NDUFV3ENST00000460259.1 linkuse as main transcriptn.997C>A non_coding_transcript_exon_variant 5/62
NDUFV3ENST00000460740.1 linkuse as main transcriptn.366C>A non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152200
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
76
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227

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 submitterclinical testingAmbry GeneticsJan 16, 2024The c.474C>A (p.S158R) alteration is located in exon 3 (coding exon 3) of the NDUFV3 gene. This alteration results from a C to A substitution at nucleotide position 474, causing the serine (S) at amino acid position 158 to be replaced by an arginine (R). 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
BayesDel_addAF
Benign
-0.099
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.69
T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
0.97
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-4.0
D
REVEL
Benign
0.16
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.42
MutPred
0.34
Loss of phosphorylation at S158 (P = 2e-04);
MVP
0.64
MPC
0.48
ClinPred
0.92
D
GERP RS
2.7
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.28
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.28
Position offset: 0

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.

Other links and lift over

dbSNP: rs777380358; hg19: chr21-44323596; API