rs886058666

Variant names:

• chr3-49022027-G-A
• rs886058666
• ENST00000451378.2:c.-95+243G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_199070.2(NDUFAF3):​c.-95+243G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000106 in 943,494 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: NDUFAF3 NM_199070.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199070.2. 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_199070.2		c.-95+243G>A		intron	N/A	NP_951033.1	Q9BU61-2
	NDUFAF3	NM_199073.2		c.-94-319G>A		intron	N/A	NP_951047.1	Q9BU61-2
	NDUFAF3	NM_199074.2		c.-94-319G>A		intron	N/A	NP_951056.1	Q9BU61-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF3	ENST00000451378.2	TSL:1	c.-95+243G>A		intron	N/A	ENSP00000402465.2	Q9BU61-2
	NDUFAF3	ENST00000886525.1		c.-118G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000556584.1
	NDUFAF3	ENST00000886525.1		c.-118G>A		5_prime_UTR	Exon 1 of 5	ENSP00000556584.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000106 AC: 1 AN: 943494 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 479002

African (AFR) AF: 0.00 AC: 0 AN: 23048

American (AMR) AF: 0.00 AC: 0 AN: 34062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20850

East Asian (EAS) AF: 0.00 AC: 0 AN: 33542

South Asian (SAS) AF: 0.00 AC: 0 AN: 66842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3188

European-Non Finnish (NFE) AF: 0.00000146 AC: 1 AN: 685372

Other (OTH) AF: 0.00 AC: 0 AN: 42940

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.85
PhyloP100		2.5
PromoterAI		-0.10	Neutral

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

Other links and lift over

dbSNP: rs886058666; hg19: chr3-49059460;