5-53646367-A-T

Variant names:

• chr5-53646367-A-T
• rs31303
• NM_002495.4:c.312A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002495.4(NDUFS4):​c.312A>T​(p.Arg104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R104R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NDUFS4 NM_002495.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.713

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS4	NM_002495.4	c.312A>T	p.Arg104Ser	missense_variant	Exon 3 of 5	ENST00000296684.10	NP_002486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS4	ENST00000296684.10	c.312A>T	p.Arg104Ser	missense_variant	Exon 3 of 5	1	NM_002495.4	ENSP00000296684.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T
Eigen	Benign	0.070
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.49		Loss of MoRF binding (P = 0.0553);.;
MVP		0.81
MPC		0.21
ClinPred		0.99	D
GERP RS		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs31303; hg19: chr5-52942197;