rs199422224

Variant names:

• chr2-206145009-T-A
• rs199422224
• NM_005006.7:c.755A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-206145009-T-A
• chr2-206145009-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The ENST00000233190.11(NDUFS1):​c.755A>T​(p.Asp252Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFS1 ENST00000233190.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-206145009-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, mitochondrial disease, mitochondrial complex I deficiency, nuclear type 5, mitochondrial complex I deficiency, Leigh syndrome with leukodystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233190.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	NM_005006.7	MANE Select	c.755A>T	p.Asp252Val	missense	Exon 9 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.797A>T	p.Asp266Val	missense	Exon 9 of 19	NP_001186913.1
	NDUFS1	NM_001199981.2		c.647A>T	p.Asp216Val	missense	Exon 8 of 18	NP_001186910.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	ENST00000233190.11	TSL:1 MANE Select	c.755A>T	p.Asp252Val	missense	Exon 9 of 19	ENSP00000233190.5
	NDUFS1	ENST00000449699.5	TSL:2	c.755A>T	p.Asp252Val	missense	Exon 9 of 19	ENSP00000399912.1
	NDUFS1	ENST00000440274.5	TSL:2	c.647A>T	p.Asp216Val	missense	Exon 8 of 18	ENSP00000409766.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.75		Gain of catalytic residue at D252 (P = 0.0308)
MVP		0.98
MPC		0.42
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.91
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs199422224; hg19: chr2-207009733;