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GeneBe

5-60945315-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.915
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.915 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
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
NDUFAF2NM_174889.5 linkuse as main transcriptc.60G>A p.Lys20= synonymous_variant 1/4 ENST00000296597.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NDUFAF2ENST00000296597.10 linkuse as main transcriptc.60G>A p.Lys20= synonymous_variant 1/41 NM_174889.5 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.636
AC:
96496
AN:
151810
Hom.:
31099
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.636
AC:
96567
AN:
151928
Hom.:
31127
Cov.:
31
AF XY:
0.639
AC XY:
47458
AN XY:
74264
show subpopulations
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:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 19, 2016- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
not specified Benign:1
Likely benign, no assertion criteria providedclinical testingGenetic 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Mitochondrial complex 1 deficiency, nuclear type 10 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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