rs567

chr5-53683267-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002495.4(NDUFS4):c.*46G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.466 in 1,335,210 control chromosomes in the GnomAD database, including 148,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14389 hom., cov: 32)
  • Exomes 𝑓: 0.47 (134134 hom.)
• Consequence: NDUFS4 NM_002495.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.79

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 5-53683267-G-A is Benign according to our data. Variant chr5-53683267-G-A is described in ClinVar as [Benign]. Clinvar id is 353892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS4	NM_002495.4	c.*46G>A		3_prime_UTR_variant	5/5	ENST00000296684.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS4	ENST00000296684.10	c.*46G>A		3_prime_UTR_variant	5/5	1	NM_002495.4	P1
NDUFS4	ENST00000506974.5	c.*350G>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	1
NDUFS4	ENST00000506765.1	c.*137G>A		3_prime_UTR_variant	4/4	2
NDUFS4	ENST00000507026.5			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64128 AN: 151692 Hom.: 14388 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.412

GnomAD3 exomes AF: 0.457 AC: 113385 AN: 248356 Hom.: 26796 AF XY: 0.458 AC XY: 61547 AN XY: 134356

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.387

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.454

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.479

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.471 AC: 557935 AN: 1183400 Hom.: 134134 Cov.: 17 AF XY: 0.472 AC XY: 284077 AN XY: 602120

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.546

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.503

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.423 AC: 64146 AN: 151810 Hom.: 14389 Cov.: 32 AF XY: 0.425 AC XY: 31492 AN XY: 74164

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.507

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.409

Alfa AF: 0.471 Hom.: 30694

Bravo AF: 0.414

Asia WGS AF: 0.361 AC: 1259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	16
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs567; hg19: chr5-52979097; COSMIC: COSV57019229; COSMIC: COSV57019229;