chr5-53646253-A-C

Position:

• chr5-53646253-A-C

Variant summary

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

The ENST00000296684.10(NDUFS4):​c.198A>C​(p.Gly66=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,611,208 control chromosomes in the GnomAD database, including 746,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G66G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (70618 hom., cov: 29)
  • Exomes 𝑓: 0.96 (675896 hom.)
• Consequence: NDUFS4 ENST00000296684.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.697

Genes affected

NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-53646253-A-C is Benign according to our data. Variant chr5-53646253-A-C is described in ClinVar as [Benign]. Clinvar id is 129700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53646253-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.697 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.198A>C	p.Gly66=	synonymous_variant	3/5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.198A>C	p.Gly66=	synonymous_variant	3/5	1	NM_002495.4	ENSP00000296684	P1

Frequencies

GnomAD3 genomes AF: 0.964 AC: 146398 AN: 151912 Hom.: 70570 Cov.: 29

Gnomad AFR AF: 0.975

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.966

Gnomad OTH AF: 0.959

GnomAD3 exomes AF: 0.955 AC: 238506 AN: 249666 Hom.: 114097 AF XY: 0.954 AC XY: 128818 AN XY: 134980

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.946

Gnomad EAS exome AF: 0.853

Gnomad SAS exome AF: 0.945

Gnomad FIN exome AF: 0.944

Gnomad NFE exome AF: 0.966

Gnomad OTH exome AF: 0.953

GnomAD4 exome AF: 0.962 AC: 1404023 AN: 1459180 Hom.: 675896 Cov.: 42 AF XY: 0.962 AC XY: 698135 AN XY: 726006

Gnomad4 AFR exome AF: 0.975

Gnomad4 AMR exome AF: 0.984

Gnomad4 ASJ exome AF: 0.945

Gnomad4 EAS exome AF: 0.852

Gnomad4 SAS exome AF: 0.946

Gnomad4 FIN exome AF: 0.942

Gnomad4 NFE exome AF: 0.968

Gnomad4 OTH exome AF: 0.958

GnomAD4 genome AF: 0.964 AC: 146502 AN: 152028 Hom.: 70618 Cov.: 29 AF XY: 0.962 AC XY: 71475 AN XY: 74284

Gnomad4 AFR AF: 0.975

Gnomad4 AMR AF: 0.978

Gnomad4 ASJ AF: 0.948

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.947

Gnomad4 FIN AF: 0.948

Gnomad4 NFE AF: 0.966

Gnomad4 OTH AF: 0.954

Alfa AF: 0.966 Hom.: 107438

Bravo AF: 0.966

Asia WGS AF: 0.898 AC: 3123 AN: 3478

EpiCase AF: 0.966

EpiControl AF: 0.967

ClinVar

Significance: Benign

Submissions summary: Benign:10

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 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2018	Variant summary: NDUFS4 c.198A>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.96 in 275374 control chromosomes, suggesting that it is the major allele (the variant most commonly observed in the general population), therefore is benign. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Leigh syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:2

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. -
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	-0.84
CADD	Benign	0.20
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs31304; hg19: chr5-52942083; COSMIC: COSV57019395;