NM_002495.4:c.177+13531A>C

Variant names:

• chr5-53617061-A-C
• rs381575
• NM_002495.4:c.177+13531A>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.177+13531A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 151,988 control chromosomes in the GnomAD database, including 13,975 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 (13975 hom., cov: 31)
• Consequence: NDUFS4 NM_002495.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 8 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.177+13531A>C		intron_variant	Intron 2 of 4	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.177+13531A>C		intron_variant	Intron 2 of 4	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63371 AN: 151870 Hom.: 13957 Cov.: 31

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.410

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

GnomAD4 genome AF: 0.417 AC: 63423 AN: 151988 Hom.: 13975 Cov.: 31 AF XY: 0.417 AC XY: 30937 AN XY: 74276

African (AFR) AF: 0.561 AC: 23225 AN: 41434

American (AMR) AF: 0.362 AC: 5533 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3470

East Asian (EAS) AF: 0.480 AC: 2478 AN: 5164

South Asian (SAS) AF: 0.473 AC: 2271 AN: 4804

European-Finnish (FIN) AF: 0.336 AC: 3541 AN: 10550

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24084 AN: 67960

Other (OTH) AF: 0.410 AC: 866 AN: 2110

Alfa AF: 0.361 Hom.: 16009

Bravo AF: 0.425

Asia WGS AF: 0.475 AC: 1651 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.11
DANN	Benign	0.53
PhyloP100		-1.6
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: rs381575; hg19: chr5-52912891;