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

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
NDUFS6NM_004553.6 linkc.29T>G p.Leu10Arg missense_variant Exon 1 of 4 ENST00000274137.10 NP_004544.1 O75380Q6IBC4
MRPL36XM_011514080.3 linkc.-80A>C upstream_gene_variant XP_011512382.1
MRPL36XM_017009751.3 linkc.-221A>C upstream_gene_variant XP_016865240.1 Q9P0J6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NDUFS6ENST00000274137.10 linkc.29T>G p.Leu10Arg missense_variant Exon 1 of 4 1 NM_004553.6 ENSP00000274137.6 O75380
NDUFS6ENST00000469176.1 linkc.29T>G p.Leu10Arg missense_variant Exon 1 of 3 2 ENSP00000422557.1 D6RBT3
NDUFS6ENST00000510329.1 linkn.26T>G non_coding_transcript_exon_variant Exon 1 of 2 3
MRPL36ENST00000505818.1 linkc.-125A>C upstream_gene_variant 3 ENSP00000427152.1 Q9P0J6

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152240
Hom.:
0
Cov.:
36
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1261905741; hg19: chr5-1801560; API