NM_025152.3:c.579A>C

Variant names:

• chr14-31787845-A-C
• rs552722349
• NM_025152.3:c.579A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_025152.3(NUBPL):​c.579A>C​(p.Leu193Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L193L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUBPL NM_025152.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.880
• Publications: 6 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)
• Leigh syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 14-31787845-A-C is Pathogenic according to our data. Variant chr14-31787845-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 50217.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	NM_025152.3	MANE Select	c.579A>C	p.Leu193Phe	missense	Exon 7 of 11	NP_079428.2
	NUBPL	NM_001201573.2		c.291A>C	p.Leu97Phe	missense	Exon 5 of 9	NP_001188502.1
	NUBPL	NM_001201574.2		c.30A>C	p.Leu10Phe	missense	Exon 2 of 6	NP_001188503.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.579A>C	p.Leu193Phe	missense	Exon 7 of 11	ENSP00000281081.7
	NUBPL	ENST00000418681.6	TSL:2	n.301A>C		non_coding_transcript_exon	Exon 2 of 6
	NUBPL	ENST00000550649.5	TSL:5	c.292-58626A>C		intron	N/A	ENSP00000447618.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.67	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	5.0	H
PhyloP100		0.88
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.85		Gain of catalytic residue at L193 (P = 0.0086)
MVP		0.65
MPC		0.57
ClinPred		1.0	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.77
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs552722349; hg19: chr14-32257051;