5-1801443-G-C

Variant names:

Variant summary

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

The NM_004553.6(NDUFS6):c.26G>C(p.Arg9Pro) 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 1,452,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 36)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NDUFS6
NM_004553.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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]

NDUFS6 links:

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]

MRPL36 links:

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
NDUFS6	NM_004553.6 link	c.26G>C	p.Arg9Pro	missense_variant	Exon 1 of 4	ENST00000274137.10	NP_004544.1	O75380Q6IBC4
MRPL36	XM_011514080.3 link	c.-77C>G		upstream_gene_variant			XP_011512382.1
MRPL36	XM_017009751.3 link	c.-218C>G		upstream_gene_variant			XP_016865240.1	Q9P0J6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFS6	ENST00000274137.10 link	c.26G>C	p.Arg9Pro	missense_variant	Exon 1 of 4	1	NM_004553.6	ENSP00000274137.6	O75380
NDUFS6	ENST00000469176.1 link	c.26G>C	p.Arg9Pro	missense_variant	Exon 1 of 3	2		ENSP00000422557.1	D6RBT3
NDUFS6	ENST00000510329.1 link	n.23G>C		non_coding_transcript_exon_variant	Exon 1 of 2	3
MRPL36	ENST00000505818.1 link	c.-122C>G		upstream_gene_variant		3		ENSP00000427152.1	Q9P0J6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000176

AC:

AN:

227172

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

126132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1452812

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000897

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000252

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 9 of the NDUFS6 protein (p.Arg9Pro). This variant is present in population databases (rs747196556, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NDUFS6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

T;.

Eigen

Benign

0.037

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.076

T;D

Sift4G

Benign

0.15

T;D

Polyphen

0.98

D;.

Vest4

0.65

MutPred

0.48

Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);

MVP

0.79

MPC

0.48

ClinPred

0.83

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.59

gMVP

0.86

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over