5-1801448-C-G

Position:

chr5-1801448-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_004553.6(NDUFS6):c.31C>G(p.Leu11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000748 in 1,605,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L11L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

NDUFS6
NM_004553.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.101

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:):

MRPL36 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016267955).

BP6

Variant 5-1801448-C-G is Benign according to our data. Variant chr5-1801448-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 726873.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152380) while in subpopulation AMR AF= 0.000457 (7/15302). AF 95% confidence interval is 0.000215. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS6	NM_004553.6 linkuse as main transcript	c.31C>G	p.Leu11Val	missense_variant	1/4	ENST00000274137.10
MRPL36	XM_011514080.3 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NDUFS6	ENST00000274137.10 linkuse as main transcript	c.31C>G	p.Leu11Val	missense_variant	1/4	1	NM_004553.6	P1
NDUFS6	ENST00000469176.1 linkuse as main transcript	c.31C>G	p.Leu11Val	missense_variant	1/3	2
NDUFS6	ENST00000510329.1 linkuse as main transcript	n.28C>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000141

AC:

AN:

227016

Hom.:

AF XY:

0.000135

AC XY:

AN XY:

126058

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000596

Gnomad OTH exome

AF:

0.000353

GnomAD4 exome

AF:

0.0000702

AC:

102

AN:

1452738

Hom.:

Cov.:

AF XY:

0.0000706

AC XY:

AN XY:

722710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00242

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000118

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.0000671

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Mitochondrial complex I deficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 20, 2020

- -

Mitochondrial complex I deficiency, nuclear type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.36

CADD

Benign

4.8

DANN

Benign

0.74

DEOGEN2

Benign

0.042

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.17

Sift

Benign

0.32

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.0020

B;.

Vest4

0.34

MutPred

0.25

Gain of MoRF binding (P = 0.0752);Gain of MoRF binding (P = 0.0752);

MVP

0.34

MPC

0.14

ClinPred

0.045

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.66

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