3-49022146-T-G

Variant names:

• chr3-49022146-T-G
• rs121918136
• NM_199069.2:c.2T>G
• NDUFAF3 p.Met1?

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.803
• Publications: 3 publications found

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]

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)

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199069.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF3	NM_199069.2	MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 5	NP_951032.1	Q9BU61-1
	NDUFAF3	NM_199070.2		c.-94-200T>G		intron	N/A	NP_951033.1	Q9BU61-2
	NDUFAF3	NM_199073.2		c.-94-200T>G		intron	N/A	NP_951047.1	Q9BU61-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF3	ENST00000326925.11	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 1 of 5	ENSP00000323076.5	Q9BU61-1
	NDUFAF3	ENST00000451378.2	TSL:1	c.-94-200T>G		intron	N/A	ENSP00000402465.2	Q9BU61-2
	DALRD3	ENST00000496568.1	TSL:2	c.-475A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000485305.1	A0A096LNZ3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456294 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724632

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111240

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.044	T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.059	D
PhyloP100		0.80
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
PromoterAI		-0.69	Under-expression
Varity_R		0.97
gMVP		0.61
Mutation Taster		=21/179	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121918136;

hg19: chr3-49059579;