rs121918135

Positions:

• chr3-49022903-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000326925.11(NDUFAF3):​c.365G>C​(p.Arg122Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFAF3 ENST00000326925.11 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.71

Genes affected

NDUFAF3 (HGNC:29918): (NADH:ubiquinone oxidoreductase complex assembly factor 3) This gene encodes a mitochondrial complex I assembly protein that interacts with complex I subunits. Mutations in this gene cause mitochondrial complex I deficiency, a fatal neonatal disorder of the oxidative phosphorylation system. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 3-49022903-G-C is Pathogenic according to our data. Variant chr3-49022903-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 423.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF3	NM_199069.2	c.365G>C	p.Arg122Pro	missense_variant	4/5	ENST00000326925.11	NP_951032.1
NDUFAF3	NM_199070.2	c.194G>C	p.Arg65Pro	missense_variant	4/5		NP_951033.1
NDUFAF3	NM_199073.2	c.194G>C	p.Arg65Pro	missense_variant	4/5		NP_951047.1
NDUFAF3	NM_199074.2	c.194G>C	p.Arg65Pro	missense_variant	4/5		NP_951056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFAF3	ENST00000326925.11	c.365G>C	p.Arg122Pro	missense_variant	4/5	1	NM_199069.2	ENSP00000323076	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 18 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T;.;.
Eigen	Benign	-0.040
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	.;T;.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.8	.;M;.;.
MutationTaster	Benign	0.98	A;A;A;A
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;N;D;D
REVEL	Pathogenic	0.66
Sift	Benign	0.096	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.027	.;B;.;.
Vest4		0.64
MutPred		0.70		.;Gain of glycosylation at T119 (P = 0.025);.;.;
MVP		0.86
MPC		1.6
ClinPred		0.79	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.92

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

Other links and lift over

dbSNP: rs121918135; hg19: chr3-49060336;