rs35462421

Variant names:

• chr2-240011654-C-T
• rs35462421
• NM_004544.4:c.712G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004544.4(NDUFA10):​c.712G>A​(p.Glu238Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00635 in 1,613,638 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (45 hom.)
• Consequence: NDUFA10 NM_004544.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.52
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.016113639).
• BP6: Variant 2-240011654-C-T is Benign according to our data. Variant chr2-240011654-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0057 (868/152294) while in subpopulation AMR AF = 0.00941 (144/15300). AF 95% confidence interval is 0.00838. There are 3 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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_004544.4. 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
	NDUFA10	NM_004544.4	MANE Select	c.712G>A	p.Glu238Lys	missense	Exon 6 of 10	NP_004535.1	O95299-1
	NDUFA10	NM_001322019.2		c.712G>A	p.Glu238Lys	missense	Exon 6 of 10	NP_001308948.1	H7C2X4
	NDUFA10	NM_001410987.1		c.712G>A	p.Glu238Lys	missense	Exon 6 of 10	NP_001397916.1	H7C1Y7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA10	ENST00000252711.7	TSL:1 MANE Select	c.712G>A	p.Glu238Lys	missense	Exon 6 of 10	ENSP00000252711.2	O95299-1
	NDUFA10	ENST00000307300.8	TSL:1	c.802G>A	p.Glu268Lys	missense	Exon 7 of 11	ENSP00000302321.4	O95299-2
	NDUFA10	ENST00000902971.1		c.832G>A	p.Glu278Lys	missense	Exon 7 of 11	ENSP00000573030.1

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 868 AN: 152176 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00895

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00579 AC: 1456 AN: 251482 AF XY: 0.00601

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00893

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00777

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00642 AC: 9384 AN: 1461344 Hom.: 45 Cov.: 30 AF XY: 0.00644 AC XY: 4684 AN XY: 727014

African (AFR) AF: 0.000687 AC: 23 AN: 33474

American (AMR) AF: 0.00890 AC: 398 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00422 AC: 364 AN: 86238

European-Finnish (FIN) AF: 0.00125 AC: 67 AN: 53414

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.00711 AC: 7905 AN: 1111512

Other (OTH) AF: 0.00750 AC: 453 AN: 60380

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152294 Hom.: 3 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74462

African (AFR) AF: 0.00127 AC: 53 AN: 41570

American (AMR) AF: 0.00941 AC: 144 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00897 AC: 610 AN: 68026

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00764 Hom.: 8

Bravo AF: 0.00639

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00535 AC: 650

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00936

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Leigh syndrome (3)
-	-	2	not specified (2)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MVP		1.0
MPC		0.68
ClinPred		0.032	T
GERP RS		4.2
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.69
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs35462421; hg19: chr2-240951071;