2-240025301-T-G

Variant names:

• chr2-240025301-T-G
• rs387906872
• NM_004544.4:c.1A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_004544.4(NDUFA10):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,353,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NDUFA10 NM_004544.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 40 codons. Genomic position: 240022298. Lost 0.110 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	NP_004535.1	O95299-1
	NDUFA10	NM_001322019.2		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	NP_001308948.1	H7C2X4
	NDUFA10	NM_001410987.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 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.1A>C	p.Met1?	initiator_codon	Exon 1 of 10	ENSP00000252711.2	O95299-1
	NDUFA10	ENST00000307300.8	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 11	ENSP00000302321.4	O95299-2
	NDUFA10	ENST00000407129.3	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000383975.3	Q8N1B9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.39e-7 AC: 1 AN: 1353110 Hom.: 0 Cov.: 33 AF XY: 0.00000150 AC XY: 1 AN XY: 667618

African (AFR) AF: 0.00 AC: 0 AN: 27380

American (AMR) AF: 0.00 AC: 0 AN: 30452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23754

East Asian (EAS) AF: 0.00 AC: 0 AN: 31340

South Asian (SAS) AF: 0.00 AC: 0 AN: 75236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1062466

Other (OTH) AF: 0.00 AC: 0 AN: 55816

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.026	N
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.078	T
PhyloP100		1.1
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.54
MutPred		0.90		Gain of stability (P = 0.0591)
MVP		0.84
ClinPred		0.99	D
GERP RS		3.0
PromoterAI		-0.44	Neutral
Varity_R		0.97
gMVP		0.65
Mutation Taster		=5/195	disease causing

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: rs387906872; hg19: chr2-240964718;