rs879255565

Variant names:

• chr14-31826682-G-GGTGCTGCCTT
• rs879255565
• NM_025152.3:c.667_668insCCTTGTGCTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_025152.3(NUBPL):​c.667_668insCCTTGTGCTG​(p.Glu223AlafsTer4) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUBPL NM_025152.3 frameshift, stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.36
• Publications: 2 publications found

Genes affected

NUBPL (HGNC:20278): (NUBP iron-sulfur cluster assembly factor, mitochondrial) This gene encodes a member of the Mrp/NBP35 ATP-binding proteins family. The encoded protein is required for the assembly of the respiratory chain NADH dehydrogenase (complex I), an oligomeric enzymatic complex located in the inner mitochondrial membrane. Mutations in this gene cause mitochondrial complex I deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

NUBPL Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 21

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-31826682-G-GGTGCTGCCTT is Pathogenic according to our data. Variant chr14-31826682-G-GGTGCTGCCTT is described in ClinVar as Pathogenic. ClinVar VariationId is 50214.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025152.3. 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
	NUBPL	NM_025152.3	MANE Select	c.667_668insCCTTGTGCTG	p.Glu223AlafsTer4	frameshift stop_gained	Exon 8 of 11	NP_079428.2	X5D2R5
	NUBPL	NM_001201573.2		c.379_380insCCTTGTGCTG	p.Glu127AlafsTer4	frameshift stop_gained	Exon 6 of 9	NP_001188502.1	B4DWB0
	NUBPL	NM_001201574.2		c.118_119insCCTTGTGCTG	p.Glu40AlafsTer4	frameshift stop_gained	Exon 3 of 6	NP_001188503.1	B3KSK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.667_668insCCTTGTGCTG	p.Glu223AlafsTer4	frameshift stop_gained	Exon 8 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.667_668insCCTTGTGCTG	p.Glu223AlafsTer4	frameshift stop_gained	Exon 8 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.661_662insCCTTGTGCTG	p.Glu221AlafsTer4	frameshift stop_gained	Exon 8 of 11	ENSP00000528736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs879255565;

hg19: chr14-32295888;