Genetic Variant NDUFA10:p.Leu294Pro (chr2-240005219-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_004544.4(NDUFA10):c.881T>C(p.Leu294Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

NDUFA10
NM_004544.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.02

Publications

3 publications found

Variant links:

Genes affected

NDUFA10 (HGNC:7684): (NADH:ubiquinone oxidoreductase subunit A10) The protein encoded by this gene is a component of 42 kDa complex I, the first enzyme complex in the electron transport chain of mitochondria. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. A mutation in this gene was found in an individual with Leigh syndrome. [provided by RefSeq, Apr 2016]

NDUFA10 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 22
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NDUFA10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 2-240005219-A-G is Pathogenic according to our data. Variant chr2-240005219-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372194.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004544.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFA10	NM_004544.4	MANE Select	c.881T>C	p.Leu294Pro	missense	Exon 8 of 10	NP_004535.1	O95299-1
NDUFA10	NM_001322019.2		c.881T>C	p.Leu294Pro	missense	Exon 8 of 10	NP_001308948.1	H7C2X4
NDUFA10	NM_001410987.1		c.881T>C	p.Leu294Pro	missense	Exon 8 of 10	NP_001397916.1	H7C1Y7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFA10	ENST00000252711.7	TSL:1 MANE Select	c.881T>C	p.Leu294Pro	missense	Exon 8 of 10	ENSP00000252711.2	O95299-1
NDUFA10	ENST00000307300.8	TSL:1	c.971T>C	p.Leu324Pro	missense	Exon 9 of 11	ENSP00000302321.4	O95299-2
NDUFA10	ENST00000902971.1		c.1001T>C	p.Leu334Pro	missense	Exon 9 of 11	ENSP00000573030.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial complex I deficiency, nuclear type 22 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.1

PhyloP100

6.0

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.95

MutPred

0.72

Loss of stability (P = 0.0059)

MVP

0.98

MPC

0.75

ClinPred

0.99

GERP RS

4.7

Varity_R

0.87

gMVP

0.87

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over