rs149271416

chr2-206141981-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_005006.7(NDUFS1):c.1222C>T(p.Arg408Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R408H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NDUFS1
NM_005006.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.59

Variant links:

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

NDUFS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-206141980-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 2-206141981-G-A is Pathogenic according to our data. Variant chr2-206141981-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 50924.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS1	NM_005006.7 linkuse as main transcript	c.1222C>T	p.Arg408Cys	missense_variant	12/19	ENST00000233190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS1	ENST00000233190.11 linkuse as main transcript	c.1222C>T	p.Arg408Cys	missense_variant	12/19	1	NM_005006.7	P1	P28331-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000795

AC:

AN:

251462

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1459074

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726092

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Alfa

AF:

0.0000307

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NDUFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 50924). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 20382551, 20819849). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs149271416, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 408 of the NDUFS1 protein (p.Arg408Cys). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2022	Observed in an apparent homozygous state in a patients with complex I deficiency/Leigh syndrome in the literature (Hoefs et al., 2010; Tuppen et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22820119, 22664328, 31589614, 30055843, 20382551, 20819849, 22142868, 36042640) -

Mitochondrial complex 1 deficiency, nuclear type 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2010

- -

NDUFS1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2022

The NDUFS1 c.1222C>T variant is predicted to result in the amino acid substitution p.Arg408Cys. This variant has been reported in the homozygous state in individuals with mitochondrial complex 1 deficiency (Hoefs et al. 2010. PubMed ID: 20382551; Tuppen et al. 2010. PubMed ID: 20819849). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-207006705-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.;.;T;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.8

H;.;.;.;.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.4

D;D;D;D;D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;D;.

Vest4

0.98

MVP

0.96

MPC

0.38

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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