NM_004553.6:c.29T>G

Variant names:

• chr5-1801446-T-G
• rs1261905741
• NM_004553.6:c.29T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004553.6(NDUFS6):​c.29T>G​(p.Leu10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 36)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NDUFS6 NM_004553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS6	NM_004553.6	c.29T>G	p.Leu10Arg	missense_variant	Exon 1 of 4	ENST00000274137.10	NP_004544.1
MRPL36	XM_011514080.3	c.-80A>C		upstream_gene_variant			XP_011512382.1
MRPL36	XM_017009751.3	c.-221A>C		upstream_gene_variant			XP_016865240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS6	ENST00000274137.10	c.29T>G	p.Leu10Arg	missense_variant	Exon 1 of 4	1	NM_004553.6	ENSP00000274137.6
NDUFS6	ENST00000469176.1	c.29T>G	p.Leu10Arg	missense_variant	Exon 1 of 3	2		ENSP00000422557.1
NDUFS6	ENST00000510329.1	n.26T>G		non_coding_transcript_exon_variant	Exon 1 of 2	3
MRPL36	ENST00000505818.1	c.-125A>C		upstream_gene_variant		3		ENSP00000427152.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452886 Hom.: 0 Cov.: 33 AF XY: 0.00000415 AC XY: 3 AN XY: 722794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 36 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.71	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.13	T;D
Sift4G	Uncertain	0.052	T;D
Polyphen		0.36	B;.
Vest4		0.71
MutPred		0.62		Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);
MVP		0.58
MPC		0.33
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.30
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1261905741; hg19: chr5-1801560;