chr15-41387519-C-T

Position:

• chr15-41387519-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016013.4(NDUFAF1):​c.909G>A​(p.Val303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,613,042 control chromosomes in the GnomAD database, including 3,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (730 hom., cov: 31)
  • Exomes 𝑓: 0.057 (3017 hom.)
• Consequence: NDUFAF1 NM_016013.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.411

Genes affected

NDUFAF1 (HGNC:18828): (NADH:ubiquinone oxidoreductase complex assembly factor 1) This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 15-41387519-C-T is Benign according to our data. Variant chr15-41387519-C-T is described in ClinVar as [Benign]. Clinvar id is 315875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.411 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF1	NM_016013.4	c.909G>A	p.Val303=	synonymous_variant	5/5	ENST00000260361.9	NP_057097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFAF1	ENST00000260361.9	c.909G>A	p.Val303=	synonymous_variant	5/5	1	NM_016013.4	ENSP00000260361	P1

Frequencies

GnomAD3 genomes AF: 0.0871 AC: 13235 AN: 152022 Hom.: 726 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0570

Gnomad OTH AF: 0.0718

GnomAD3 exomes AF: 0.0680 AC: 17095 AN: 251386 Hom.: 826 AF XY: 0.0612 AC XY: 8312 AN XY: 135888

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0970

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.0203

Gnomad FIN exome AF: 0.0342

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0531

GnomAD4 exome AF: 0.0570 AC: 83288 AN: 1460902 Hom.: 3017 Cov.: 32 AF XY: 0.0551 AC XY: 40021 AN XY: 726824

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0941

Gnomad4 ASJ exome AF: 0.0360

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.0205

Gnomad4 FIN exome AF: 0.0360

Gnomad4 NFE exome AF: 0.0529

Gnomad4 OTH exome AF: 0.0578

GnomAD4 genome AF: 0.0872 AC: 13262 AN: 152140 Hom.: 730 Cov.: 31 AF XY: 0.0847 AC XY: 6301 AN XY: 74382

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0678

Gnomad4 ASJ AF: 0.0386

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.0570

Gnomad4 OTH AF: 0.0715

Alfa AF: 0.0681 Hom.: 236

Bravo AF: 0.0945

Asia WGS AF: 0.0690 AC: 241 AN: 3478

EpiCase AF: 0.0551

EpiControl AF: 0.0525

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.83
DANN	Benign	0.54

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: rs73407109; hg19: chr15-41679717;