5-53588734-G-A

Variant names:

• chr5-53588734-G-A
• rs2168662
• NM_002495.4:c.99-14718G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002495.4(NDUFS4):​c.99-14718G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 152,052 control chromosomes in the GnomAD database, including 14,410 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14410 hom., cov: 33)
• Consequence: NDUFS4 NM_002495.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 5 publications found

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]

NDUFS4 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency, nuclear type

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002495.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	NM_002495.4	MANE Select	c.99-14718G>A		intron	N/A	NP_002486.1
	NDUFS4	NM_001318051.2		c.99-14718G>A		intron	N/A	NP_001304980.1
	NDUFS4	NR_134473.2		n.123-14718G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.99-14718G>A		intron	N/A	ENSP00000296684.5
	NDUFS4	ENST00000506974.5	TSL:1	n.99-14718G>A		intron	N/A	ENSP00000425967.1
	NDUFS4	ENST00000506765.1	TSL:2	c.87-14718G>A		intron	N/A	ENSP00000424570.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64291 AN: 151936 Hom.: 14410 Cov.: 33

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.412

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.423 AC: 64308 AN: 152052 Hom.: 14410 Cov.: 33 AF XY: 0.425 AC XY: 31591 AN XY: 74314

African (AFR) AF: 0.288 AC: 11939 AN: 41478

American (AMR) AF: 0.503 AC: 7689 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1367 AN: 3470

East Asian (EAS) AF: 0.283 AC: 1460 AN: 5168

South Asian (SAS) AF: 0.445 AC: 2145 AN: 4820

European-Finnish (FIN) AF: 0.503 AC: 5307 AN: 10544

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.486 AC: 33020 AN: 67960

Other (OTH) AF: 0.409 AC: 865 AN: 2114

Alfa AF: 0.454 Hom.: 2023

Bravo AF: 0.415

Asia WGS AF: 0.361 AC: 1259 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.4
DANN	Benign	0.28
PhyloP100		0.042
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2168662; hg19: chr5-52884564;