5-60945315-G-A

Position:

• chr5-60945315-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_174889.5(NDUFAF2):​c.60G>A​(p.Lys20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,547,454 control chromosomes in the GnomAD database, including 241,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31127 hom., cov: 31)
  • Exomes 𝑓: 0.58 (210605 hom.)
• Consequence: NDUFAF2 NM_174889.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.915

Genes affected

NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) 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. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 5-60945315-G-A is Benign according to our data. Variant chr5-60945315-G-A is described in ClinVar as [Benign]. Clinvar id is 129691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60945315-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.915 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF2	NM_174889.5	c.60G>A	p.Lys20=	synonymous_variant	1/4	ENST00000296597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF2	ENST00000296597.10	c.60G>A	p.Lys20=	synonymous_variant	1/4	1	NM_174889.5	P1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96496 AN: 151810 Hom.: 31099 Cov.: 31

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.823

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.619

GnomAD3 exomes AF: 0.650 AC: 159574 AN: 245620 Hom.: 52304 AF XY: 0.644 AC XY: 85508 AN XY: 132758

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.753

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.939

Gnomad SAS exome AF: 0.658

Gnomad FIN exome AF: 0.593

Gnomad NFE exome AF: 0.594

Gnomad OTH exome AF: 0.614

GnomAD4 exome AF: 0.576 AC: 803812 AN: 1395526 Hom.: 210605 Cov.: 61 AF XY: 0.578 AC XY: 402838 AN XY: 696378

Gnomad4 AFR exome AF: 0.589

Gnomad4 AMR exome AF: 0.740

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.933

Gnomad4 SAS exome AF: 0.638

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.549

Gnomad4 OTH exome AF: 0.588

GnomAD4 genome AF: 0.636 AC: 96567 AN: 151928 Hom.: 31127 Cov.: 31 AF XY: 0.639 AC XY: 47458 AN XY: 74264

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.683

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.943

Gnomad4 SAS AF: 0.671

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.605

Gnomad4 OTH AF: 0.622

Alfa AF: 0.606 Hom.: 9594

Bravo AF: 0.641

Asia WGS AF: 0.818 AC: 2845 AN: 3478

EpiCase AF: 0.600

EpiControl AF: 0.597

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Cockayne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mitochondrial complex 1 deficiency, nuclear type 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.92

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: rs158921; hg19: chr5-60241142; COSMIC: COSV54016491; COSMIC: COSV54016491;