rs189848

Variant names:

• chr5-53662727-G-A
• rs189848
• NM_002495.4:c.424+4103G>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.424+4103G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 151,794 control chromosomes in the GnomAD database, including 3,638 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 (3638 hom., cov: 31)
• Consequence: NDUFS4 NM_002495.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.171
• Publications: 2 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=-0.91).
• 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.424+4103G>A		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.424+4103G>A		intron_variant	Intron 4 of 4	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30796 AN: 151676 Hom.: 3639 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.209

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

GnomAD4 genome AF: 0.203 AC: 30811 AN: 151794 Hom.: 3638 Cov.: 31 AF XY: 0.205 AC XY: 15235 AN XY: 74146

African (AFR) AF: 0.287 AC: 11879 AN: 41352

American (AMR) AF: 0.194 AC: 2966 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 621 AN: 3468

East Asian (EAS) AF: 0.465 AC: 2391 AN: 5146

South Asian (SAS) AF: 0.263 AC: 1261 AN: 4798

European-Finnish (FIN) AF: 0.135 AC: 1417 AN: 10532

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

European-Non Finnish (NFE) AF: 0.143 AC: 9728 AN: 67910

Other (OTH) AF: 0.211 AC: 444 AN: 2108

Alfa AF: 0.177 Hom.: 367

Bravo AF: 0.212

Asia WGS AF: 0.334 AC: 1158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.26
PhyloP100		0.17
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: rs189848; hg19: chr5-52958557;