rs13156337

Variant names:

• chr5-53568965-T-C
• rs13156337
• NM_002495.4:c.98+8205T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002495.4(NDUFS4):​c.98+8205T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0757 in 152,278 control chromosomes in the GnomAD database, including 550 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 0.076 (550 hom., cov: 32)
• Consequence: NDUFS4 NM_002495.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	NM_002495.4	MANE Select	c.98+8205T>C		intron	N/A	NP_002486.1
	NDUFS4	NM_001318051.2		c.98+8205T>C		intron	N/A	NP_001304980.1
	NDUFS4	NR_134473.2		n.122+8205T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.98+8205T>C		intron	N/A	ENSP00000296684.5
	NDUFS4	ENST00000506974.5	TSL:1	n.98+8205T>C		intron	N/A	ENSP00000425967.1
	NDUFS4	ENST00000856911.1		c.98+8205T>C		intron	N/A	ENSP00000526970.1

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11538 AN: 152160 Hom.: 549 Cov.: 32

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.0485

Gnomad AMR AF: 0.0917

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0480

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.0757 AC: 11532 AN: 152278 Hom.: 550 Cov.: 32 AF XY: 0.0757 AC XY: 5637 AN XY: 74460

African (AFR) AF: 0.0241 AC: 1001 AN: 41586

American (AMR) AF: 0.0915 AC: 1400 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3472

East Asian (EAS) AF: 0.00250 AC: 13 AN: 5192

South Asian (SAS) AF: 0.0481 AC: 232 AN: 4828

European-Finnish (FIN) AF: 0.103 AC: 1098 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7061 AN: 67976

Other (OTH) AF: 0.100 AC: 212 AN: 2112

Alfa AF: 0.0673 Hom.: 184

Bravo AF: 0.0727

Asia WGS AF: 0.0350 AC: 120 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		3.4
Mutation Taster		=97/3	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: rs13156337; hg19: chr5-52864795;