5-1801448-C-A

Variant names:

• chr5-1801448-C-A
• rs755222875
• NM_004553.6:c.31C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004553.6(NDUFS6):​c.31C>A​(p.Leu11Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,452,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L11V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NDUFS6 NM_004553.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• Publications: 0 publications found

Genes affected

NDUFS6 (HGNC:7713): (NADH:ubiquinone oxidoreductase subunit S6) This gene encodes a subunit of the NADH:ubiquinone oxidoreductase (complex I), which is the first enzyme complex in the electron transport chain of mitochondria. This complex functions in the transfer of electrons from NADH to the respiratory chain. The subunit encoded by this gene is one of seven subunits in the iron-sulfur protein fraction. Mutations in this gene cause mitochondrial complex I deficiency, a disease that causes a wide variety of clinical disorders, including neonatal disease and adult-onset neurodegenerative disorders.[provided by RefSeq, Oct 2009]

MRPL36 (HGNC:14490): (mitochondrial ribosomal protein L36) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. A pseudogene corresponding to this gene is found on chromosome 2p. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2664435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004553.6. 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
	NDUFS6	NM_004553.6	MANE Select	c.31C>A	p.Leu11Met	missense	Exon 1 of 4	NP_004544.1	Q6IBC4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS6	ENST00000274137.10	TSL:1 MANE Select	c.31C>A	p.Leu11Met	missense	Exon 1 of 4	ENSP00000274137.6	O75380
	NDUFS6	ENST00000933864.1		c.31C>A	p.Leu11Met	missense	Exon 1 of 4	ENSP00000603923.1
	NDUFS6	ENST00000469176.1	TSL:2	c.31C>A	p.Leu11Met	missense	Exon 1 of 3	ENSP00000422557.1	D6RBT3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452738 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 722710

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110638

Other (OTH) AF: 0.00 AC: 0 AN: 60068

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-0.10
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.40
Sift	Benign	0.040	D
Sift4G	Uncertain	0.038	D
Polyphen		0.93	P
Vest4		0.47
MutPred		0.42		Gain of catalytic residue at L11 (P = 0.0077)
MVP		0.34
MPC		0.51
ClinPred		0.91	D
GERP RS		1.3
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.086
gMVP		0.60
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs755222875; hg19: chr5-1801562;