rs1388111

Variant names:

• chr5-53649428-T-C
• rs1388111
• NM_002495.4:c.350+3023T>C

Variant summary

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

The NM_002495.4(NDUFS4):​c.350+3023T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,074 control chromosomes in the GnomAD database, including 5,911 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 0.26 (5911 hom., cov: 32)
• Consequence: NDUFS4 NM_002495.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.489
• Publications: 9 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 = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.350+3023T>C		intron_variant	Intron 3 of 4	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.350+3023T>C		intron_variant	Intron 3 of 4	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39943 AN: 151956 Hom.: 5910 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.263 AC: 39955 AN: 152074 Hom.: 5911 Cov.: 32 AF XY: 0.265 AC XY: 19724 AN XY: 74336

African (AFR) AF: 0.139 AC: 5770 AN: 41514

American (AMR) AF: 0.349 AC: 5333 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1032 AN: 3472

East Asian (EAS) AF: 0.130 AC: 673 AN: 5176

South Asian (SAS) AF: 0.296 AC: 1424 AN: 4812

European-Finnish (FIN) AF: 0.339 AC: 3584 AN: 10558

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21379 AN: 67966

Other (OTH) AF: 0.249 AC: 523 AN: 2104

Alfa AF: 0.297 Hom.: 19805

Bravo AF: 0.258

Asia WGS AF: 0.212 AC: 743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.56
PhyloP100		0.49
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: rs1388111; hg19: chr5-52945258;