ENST00000451378.2:c.-95+120C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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, 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 -12 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.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000451378.2. 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;