2-206138586-G-C

Variant names:

• chr2-206138586-G-C
• rs78042826
• NM_005006.7:c.1291C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005006.7(NDUFS1):​c.1291C>G​(p.Leu431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,613,942 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. L431F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (16 hom.)
• Consequence: NDUFS1 NM_005006.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 3.18
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.075123 (below the threshold of 3.09). Trascript score misZ: 0.57926 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial complex I deficiency, mitochondrial complex I deficiency, nuclear type 5, mitochondrial disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014639646).
• BP6: Variant 2-206138586-G-C is Benign according to our data. Variant chr2-206138586-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138479.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (511/152236) while in subpopulation NFE AF = 0.00531 (361/68020). AF 95% confidence interval is 0.00486. There are 3 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005006.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	NM_005006.7	MANE Select	c.1291C>G	p.Leu431Val	missense	Exon 13 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.1333C>G	p.Leu445Val	missense	Exon 13 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.1183C>G	p.Leu395Val	missense	Exon 12 of 18	NP_001186910.1	P28331-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	ENST00000233190.11	TSL:1 MANE Select	c.1291C>G	p.Leu431Val	missense	Exon 13 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903706.1		c.1291C>G	p.Leu431Val	missense	Exon 13 of 19	ENSP00000573765.1
	NDUFS1	ENST00000449699.5	TSL:2	c.1291C>G	p.Leu431Val	missense	Exon 13 of 19	ENSP00000399912.1	P28331-1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152118 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00330 AC: 830 AN: 251486 AF XY: 0.00324

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00437 AC: 6381 AN: 1461706 Hom.: 16 Cov.: 31 AF XY: 0.00426 AC XY: 3098 AN XY: 727166

African (AFR) AF: 0.000597 AC: 20 AN: 33476

American (AMR) AF: 0.00291 AC: 130 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86250

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00524 AC: 5830 AN: 1111866

Other (OTH) AF: 0.00412 AC: 249 AN: 60390

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152236 Hom.: 3 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74430

African (AFR) AF: 0.00101 AC: 42 AN: 41544

American (AMR) AF: 0.00511 AC: 78 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00531 AC: 361 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00445 Hom.: 1

Bravo AF: 0.00337

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00356 AC: 432

EpiCase AF: 0.00431

EpiControl AF: 0.00439

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	-	2	Mitochondrial complex I deficiency (2)
-	1	-	Leigh syndrome (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 5 (1)
-	-	1	NDUFS1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.20
Sift	Benign	0.73	T
Sift4G	Benign	0.82	T
Polyphen		0.0050	B
Vest4		0.33
MVP		0.81
MPC		0.057
ClinPred		0.016	T
GERP RS		4.1
Varity_R		0.13
gMVP		0.62
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs78042826; hg19: chr2-207003310; COSMIC: COSV99028509;