5-53679900-A-G

Variant names:

• chr5-53679900-A-G
• rs445347
• NM_002495.4:c.425-3218A>G

Variant summary

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

The NM_002495.4(NDUFS4):​c.425-3218A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 151,898 control chromosomes in the GnomAD database, including 3,698 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 0.20 (3698 hom., cov: 32)
• Consequence: NDUFS4 NM_002495.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 4 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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.425-3218A>G		intron_variant	Intron 4 of 4	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.425-3218A>G		intron_variant	Intron 4 of 4	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31075 AN: 151780 Hom.: 3698 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.210

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

GnomAD4 genome AF: 0.205 AC: 31096 AN: 151898 Hom.: 3698 Cov.: 32 AF XY: 0.207 AC XY: 15374 AN XY: 74244

African (AFR) AF: 0.290 AC: 12018 AN: 41416

American (AMR) AF: 0.195 AC: 2966 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 633 AN: 3472

East Asian (EAS) AF: 0.465 AC: 2393 AN: 5150

South Asian (SAS) AF: 0.268 AC: 1288 AN: 4806

European-Finnish (FIN) AF: 0.136 AC: 1439 AN: 10582

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9808 AN: 67914

Other (OTH) AF: 0.212 AC: 447 AN: 2112

Alfa AF: 0.165 Hom.: 1182

Bravo AF: 0.214

Asia WGS AF: 0.338 AC: 1173 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		-0.030
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: rs445347; hg19: chr5-52975730;