chr3-49021904-C-T

Variant names:

• chr3-49021904-C-T
• rs573066357
• ENST00000451378.2:c.-95+120C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_199070.2(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 NM_199070.2 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.50
• 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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+120C>T		intron	N/A	NP_951033.1	Q9BU61-2
	NDUFAF3	NM_199073.2		c.-94-442C>T		intron	N/A	NP_951047.1	Q9BU61-2
	NDUFAF3	NM_199074.2		c.-94-442C>T		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+120C>T		intron	N/A	ENSP00000402465.2	Q9BU61-2
	NDUFAF3	ENST00000886525.1		c.-241C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000556584.1
	NDUFAF3	ENST00000886525.1		c.-241C>T		5_prime_UTR	Exon 1 of 5	ENSP00000556584.1

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

African (AFR) AF: 0.00142 AC: 14 AN: 9892

American (AMR) AF: 0.00193 AC: 33 AN: 17084

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 184 AN: 12814

East Asian (EAS) AF: 0.0000356 AC: 1 AN: 28108

South Asian (SAS) AF: 0.00415 AC: 184 AN: 44338

European-Finnish (FIN) AF: 0.00163 AC: 47 AN: 28846

Middle Eastern (MID) AF: 0.0111 AC: 21 AN: 1886

European-Non Finnish (NFE) AF: 0.00369 AC: 954 AN: 258424

Other (OTH) AF: 0.00410 AC: 102 AN: 24868

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

African (AFR) AF: 0.00166 AC: 69 AN: 41590

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00274

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.85
PhyloP100		-2.5
PromoterAI		0.018	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs573066357; hg19: chr3-49059337;