2-240022311-T-C

Variant names:

• chr2-240022311-T-C
• rs2083411
• NM_004544.4:c.105A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004544.4(NDUFA10):​c.105A>G​(p.Lys35Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,613,746 control chromosomes in the GnomAD database, including 356,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37377 hom., cov: 31)
  • Exomes 𝑓: 0.66 (318674 hom.)
• Consequence: NDUFA10 NM_004544.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.111
• Publications: 26 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-240022311-T-C is Benign according to our data. Variant chr2-240022311-T-C is described in ClinVar as Benign. ClinVar VariationId is 129685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.111 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

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.105A>G	p.Lys35Lys	synonymous	Exon 2 of 10	NP_004535.1
	NDUFA10	NM_001322019.2		c.105A>G	p.Lys35Lys	synonymous	Exon 2 of 10	NP_001308948.1
	NDUFA10	NM_001410987.1		c.105A>G	p.Lys35Lys	synonymous	Exon 2 of 10	NP_001397916.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA10	ENST00000252711.7	TSL:1 MANE Select	c.105A>G	p.Lys35Lys	synonymous	Exon 2 of 10	ENSP00000252711.2
	NDUFA10	ENST00000307300.8	TSL:1	c.105A>G	p.Lys35Lys	synonymous	Exon 2 of 11	ENSP00000302321.4
	NDUFA10	ENST00000407129.3	TSL:1	c.105A>G	p.Lys35Lys	synonymous	Exon 2 of 4	ENSP00000383975.3

Frequencies

GnomAD3 genomes AF: 0.698 AC: 105989 AN: 151898 Hom.: 37333 Cov.: 31

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.665

GnomAD2 exomes AF: 0.665 AC: 167260 AN: 251376 AF XY: 0.661

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.639

Gnomad EAS exome AF: 0.781

Gnomad FIN exome AF: 0.730

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.640

GnomAD4 exome AF: 0.659 AC: 962856 AN: 1461730 Hom.: 318674 Cov.: 49 AF XY: 0.655 AC XY: 476389 AN XY: 727172

African (AFR) AF: 0.791 AC: 26466 AN: 33480

American (AMR) AF: 0.635 AC: 28415 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 16669 AN: 26130

East Asian (EAS) AF: 0.734 AC: 29118 AN: 39686

South Asian (SAS) AF: 0.581 AC: 50077 AN: 86254

European-Finnish (FIN) AF: 0.726 AC: 38745 AN: 53404

Middle Eastern (MID) AF: 0.559 AC: 3227 AN: 5768

European-Non Finnish (NFE) AF: 0.657 AC: 730308 AN: 1111894

Other (OTH) AF: 0.660 AC: 39831 AN: 60390

GnomAD4 genome AF: 0.698 AC: 106092 AN: 152016 Hom.: 37377 Cov.: 31 AF XY: 0.700 AC XY: 51978 AN XY: 74292

African (AFR) AF: 0.795 AC: 32952 AN: 41448

American (AMR) AF: 0.661 AC: 10105 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2242 AN: 3466

East Asian (EAS) AF: 0.762 AC: 3928 AN: 5154

South Asian (SAS) AF: 0.576 AC: 2774 AN: 4812

European-Finnish (FIN) AF: 0.734 AC: 7751 AN: 10560

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44144 AN: 67986

Other (OTH) AF: 0.663 AC: 1400 AN: 2112

Alfa AF: 0.663 Hom.: 134596

Bravo AF: 0.697

Asia WGS AF: 0.663 AC: 2304 AN: 3478

EpiCase AF: 0.642

EpiControl AF: 0.647

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.0
DANN	Benign	0.44
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2083411; hg19: chr2-240961728; COSMIC: COSV53156790;