rs1057519415

Variant names:

• chr2-240021272-A-AATT
• rs1057519415
• NM_004544.4:c.384_385insAAT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_004544.4(NDUFA10):​c.384_385insAAT​(p.Ser128dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFA10 NM_004544.4 conservative_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.545
• 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004544.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-240021272-A-AATT is Pathogenic according to our data. Variant chr2-240021272-A-AATT is described in ClinVar as Pathogenic. ClinVar VariationId is 372195.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA10	NM_004544.4	MANE Select	c.384_385insAAT	p.Ser128dup	conservative_inframe_insertion	Exon 3 of 10	NP_004535.1
	NDUFA10	NM_001322019.2		c.384_385insAAT	p.Ser128dup	conservative_inframe_insertion	Exon 3 of 10	NP_001308948.1
	NDUFA10	NM_001410987.1		c.384_385insAAT	p.Ser128dup	conservative_inframe_insertion	Exon 3 of 10	NP_001397916.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA10	ENST00000252711.7	TSL:1 MANE Select	c.384_385insAAT	p.Ser128dup	conservative_inframe_insertion	Exon 3 of 10	ENSP00000252711.2
	NDUFA10	ENST00000307300.8	TSL:1	c.384_385insAAT	p.Ser128dup	conservative_inframe_insertion	Exon 3 of 11	ENSP00000302321.4
	NDUFA10	ENST00000407129.3	TSL:1	c.384_385insAAT	p.Ser128dup	conservative_inframe_insertion	Exon 3 of 4	ENSP00000383975.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 22 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.55
Mutation Taster		=64/36	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519415; hg19: chr2-240960689;