chr14-31599310-G-C

Variant names:

• chr14-31599310-G-C
• rs397515440
• NM_025152.3:c.313G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_025152.3(NUBPL):​c.313G>C​(p.Asp105His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D105Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUBPL NM_025152.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.92
• Publications: 9 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-31599310-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50215.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

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.313G>C	p.Asp105His	missense	Exon 4 of 11	NP_079428.2	X5D2R5
	NUBPL	NM_001201573.2		c.25G>C	p.Asp9His	missense	Exon 2 of 9	NP_001188502.1	B4DWB0
	NUBPL	NR_120408.2		n.349G>C		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.313G>C	p.Asp105His	missense	Exon 4 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.313G>C	p.Asp105His	missense	Exon 4 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.307G>C	p.Asp103His	missense	Exon 4 of 11	ENSP00000528736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		6.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Loss of catalytic residue at D105 (P = 0.1483)
MVP		0.86
MPC		0.61
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.94
Mutation Taster		=26/74	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: rs397515440; hg19: chr14-32068516; COSMIC: COSV108012486;