Genetic Variant NDUFAF3:p.Met1? (chr3-49022146-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_199069.2(NDUFAF3):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NDUFAF3
NM_199069.2 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.803

Publications

3 publications found

Variant links:

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]

NDUFAF3 links:

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]

DALRD3 Gene-Disease associations (from GenCC):

undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
developmental and epileptic encephalopathy, 86
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)

DALRD3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 58 codons. Genomic position: 49022440. Lost 0.310 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF3	NM_199069.2 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 5	ENST00000326925.11	NP_951032.1	Q9BU61-1Q9Y3Z0
NDUFAF3	NM_199070.2 link	c.-94-200T>G		intron_variant	Intron 1 of 4		NP_951033.1	A4FU71Q9Y3Z0
NDUFAF3	NM_199073.2 link	c.-94-200T>G		intron_variant	Intron 1 of 4		NP_951047.1	A4FU71
NDUFAF3	NM_199074.2 link	c.-94-200T>G		intron_variant	Intron 1 of 4		NP_951056.1	A4FU71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF3	ENST00000326925.11 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 5	1	NM_199069.2	ENSP00000323076.5		Q9BU61-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456294

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.00

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111240

Other (OTH)

AF:

0.00

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.044

Eigen

Benign

0.021

Eigen_PC

Benign

-0.054

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.059

PhyloP100

0.80

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.94

Vest4

0.75

MutPred

0.99

Gain of methylation at M1 (P = 0.0022);

MVP

0.83

ClinPred

0.99

GERP RS

2.6

PromoterAI

-0.69

Under-expression

(source)

Varity_R

0.97

gMVP

0.61

Mutation Taster

=21/179

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over