3-49021904-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000451378.2(NDUFAF3):c.-95+120C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 578,570 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (5 hom.)
• Consequence: NDUFAF3 ENST00000451378.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.50

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0028 (427/152310) while in subpopulation SAS AF= 0.00518 (25/4830). AF 95% confidence interval is 0.0036. There are 2 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF3	NM_199070.2	c.-95+120C>T		intron_variant
NDUFAF3	NM_199073.2	c.-94-442C>T		intron_variant
NDUFAF3	NM_199074.2	c.-94-442C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF3	ENST00000451378.2	c.-95+120C>T		intron_variant		1
NDUFAF3	ENST00000326912.8	c.-94-442C>T		intron_variant		2
NDUFAF3	ENST00000395458.6	c.-94-442C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00361 AC: 1540 AN: 426260 Hom.: 5 Cov.: 4 AF XY: 0.00373 AC XY: 837 AN XY: 224476

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.0000356

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.00369

Gnomad4 OTH exome AF: 0.00410

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74466

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00274

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.16
Dann	Benign	0.85

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: rs573066357; hg19: chr3-49059337;