5-1801432-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_004553.6(NDUFS6):c.15G>A(p.Met5Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,605,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 36)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NDUFS6
NM_004553.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.83

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10948154).

BP6

Variant 5-1801432-G-A is Benign according to our data. Variant chr5-1801432-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2153173.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS6	NM_004553.6 link	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 4	ENST00000274137.10	NP_004544.1	O75380Q6IBC4
MRPL36	XM_011514080.3 link	c.-66C>T		5_prime_UTR_variant	Exon 1 of 2		XP_011512382.1
MRPL36	XM_017009751.3 link	c.-207C>T		upstream_gene_variant			XP_016865240.1	Q9P0J6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFS6	ENST00000274137.10 link	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 4	1	NM_004553.6	ENSP00000274137.6	O75380
NDUFS6	ENST00000469176.1 link	c.15G>A	p.Met5Ile	missense_variant	Exon 1 of 3	2		ENSP00000422557.1	D6RBT3
NDUFS6	ENST00000510329.1 link	n.12G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3
MRPL36	ENST00000505818.1 link	c.-111C>T		upstream_gene_variant		3		ENSP00000427152.1	Q9P0J6

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000880

AC:

AN:

227152

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126170

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00

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:

0.0000213

AC:

AN:

1452826

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

722680

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000240

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.00000840

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.15G>A (p.M5I) alteration is located in exon 1 (coding exon 1) of the NDUFS6 gene. This alteration results from a G to A substitution at nucleotide position 15, causing the methionine (M) at amino acid position 5 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 5 of the NDUFS6 protein (p.Met5Ile). This variant is present in population databases (rs374411074, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NDUFS6-related conditions. ClinVar contains an entry for this variant (Variation ID: 2153173). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Mitochondrial complex 1 deficiency, nuclear type 9

Benign:1

Sep 20, 2024

3billion

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.26

N;N

REVEL

Benign

0.13

Sift

Benign

0.42

T;D

Sift4G

Benign

0.57

T;T

Polyphen

0.0

B;.

Vest4

0.17

MutPred

0.36

Loss of disorder (P = 0.0217);Loss of disorder (P = 0.0217);

MVP

0.43

MPC

0.15

ClinPred

0.78

GERP RS

3.2

Varity_R

0.27

gMVP

0.30

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