chr14-31561441-T-C

Position:

chr14-31561441-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000281081.12(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
ENST00000281081.12 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.09

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
NUBPL	NM_025152.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/11	ENST00000281081.12	NP_079428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUBPL	ENST00000281081.12 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/11	1	NM_025152.3	ENSP00000281081	P1	Q8TB37-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

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:

AN:

135226

Hom.:

AF XY:

0.000107

AC XY:

AN XY:

74808

show subpopulations

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:

AN:

1250180

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

610852

show subpopulations

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:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74440

show subpopulations

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.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000913

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.0090

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.59

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over