3-49022188-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_199069.2(NDUFAF3):c.44C>T(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFAF3 NM_199069.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0370

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]

DALRD3 (HGNC:25536): (DALR anticodon binding domain containing 3) The exact function of this gene is not known. It encodes a protein with a DALR anticodon binding domain similar to that of class Ia aminoacyl tRNA synthetases. This gene is located in a cluster of genes (with a complex sense-anti-sense genome architecture) on chromosome 3, and contains two micro RNA (miRNA) precursors (mir-425 and mir-191) in one of its introns. Preferential expression of this gene (the miRNAs and other genes in the cluster) in testis suggests a role of this gene in spermatogenesis (PMID:19906709). [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055447668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF3	NM_199069.2	c.44C>T	p.Pro15Leu	missense_variant	1/5	ENST00000326925.11
NDUFAF3	NM_199070.2	c.-94-158C>T		intron_variant
NDUFAF3	NM_199073.2	c.-94-158C>T		intron_variant
NDUFAF3	NM_199074.2	c.-94-158C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF3	ENST00000326925.11	c.44C>T	p.Pro15Leu	missense_variant	1/5	1	NM_199069.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458360 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725676

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.44C>T (p.P15L) alteration is located in exon 1 (coding exon 1) of the NDUFAF3 gene. This alteration results from a C to T substitution at nucleotide position 44, causing the proline (P) at amino acid position 15 to be replaced by a leucine (L). 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	0.087
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	8.4
Dann	Benign	0.77
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.11
Sift	Benign	0.36	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.36		Loss of loop (P = 9e-04);
MVP		0.35
MPC		0.50
ClinPred		0.15	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.32

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: rs1262103940; hg19: chr3-49059621;