14-31561441-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_025152.3(NUBPL):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,402,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: NUBPL NM_025152.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-31561441-T-C is Pathogenic according to our data. Variant chr14-31561441-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUBPL	NM_025152.3	c.2T>C	p.Met1?	start_lost	1/11	ENST00000281081.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUBPL	ENST00000281081.12	c.2T>C	p.Met1?	start_lost	1/11	1	NM_025152.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000104 AC: 14 AN: 135226 Hom.: 0 AF XY: 0.000107 AC XY: 8 AN XY: 74808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000645

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000381

GnomAD4 exome AF: 0.0000328 AC: 41 AN: 1250180 Hom.: 0 Cov.: 29 AF XY: 0.0000377 AC XY: 23 AN XY: 610852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000887

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000485

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000601

Gnomad4 OTH exome AF: 0.000160

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000913 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 21 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The initiator codon variant p.M1T in NUBPL (NM_025152.3) has been reported to ClinVar as Likely Pathogenic. This variant is predicted to severely affect the synthesis of the NUBPL protein by disrupting the translation initiation start codon (ATG), resulting in a truncated or absent protein. The p.M1T variant has a GnomAD frequency of 0.01035 %. The p.M1T variant is a loss of function variant in the gene NUBPL, which is intolerant of Loss of Function variants. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The nucleotide change in NUBPL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -

Mitochondrial oxidative phosphorylation disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2017

The p.Met1? (NM_025152.2 c.2T>C) variant in NUBPL has not been reported in indiv iduals with clinical features of mitochondrial complex I deficiency. This varian t has been identified in 0.14% (6/4298) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs567437692) . While its precise impact is not known, this variant is predicted to severely a ffect the synthesis of the NUBPL protein by disrupting the translation initiatio n start codon (ATG), resulting in a truncated or absent protein. Biallelic loss of function in the NUBPL gene has been associated with mitochondrial complex I d eficiency. In summary, although additional studies are required to fully establi sh a null effect, the p.Met1? variant is likely pathogenic for mitochondrial com plex I deficiency in an autosomal recessive manner based on its predicted functi onal impact. -

Mitochondrial complex I deficiency, nuclear type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The start loss variant c.2T>C(p.Met1?) in NUBPL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.01%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Likely Pathogenic. The p.Met1? variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. No significant variant in the NUBPL gene has been detected in the spouse. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	21
Dann	Benign	0.92
DEOGEN2	Benign	0.0090	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.47	N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.93	.;P
Vest4		0.85
MutPred		0.92		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.71
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs567437692; hg19: chr14-32030647;