chr14-31561441-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_ModeratePP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

NUBPL
NM_025152.3 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 2.09

Publications

1 publications found

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:

NUBPL-DT (HGNC:55483): (NUBPL divergent transcript)

NUBPL-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 31 codons. Genomic position: 31561530. Lost 0.095 part of the original CDS.

PP5

Variant 14-31561441-T-C is Pathogenic according to our data. Variant chr14-31561441-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517222.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NUBPL	NM_025152.3 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENST00000281081.12	NP_079428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUBPL	ENST00000281081.12 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11	1	NM_025152.3	ENSP00000281081.7

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

GnomAD2 exomes

AF:

0.000104

AC:

AN:

135226

AF XY:

0.000107

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 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

African (AFR)

AF:

0.00

AC:

AN:

26080

American (AMR)

AF:

0.0000887

AC:

AN:

22544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18700

East Asian (EAS)

AF:

0.00

AC:

AN:

31066

South Asian (SAS)

AF:

0.000485

AC:

AN:

51520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4976

European-Non Finnish (NFE)

AF:

0.00000601

AC:

AN:

998466

Other (OTH)

AF:

0.000160

AC:

AN:

50142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000342

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000913

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 21

Pathogenic:1Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The current evidence is insufficient to determine the pathogenicity of the variant conclusively.

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mitochondrial oxidative phosphorylation disorder

Pathogenic:1

Mar 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0090

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.33

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.0

.;.

PhyloP100

2.1

PROVEAN

Benign

-0.47

N;N

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.0

ClinPred

0.98

GERP RS

5.3

PromoterAI

-0.13

Neutral

(source)

Varity_R

0.94

gMVP

0.66

Mutation Taster

=36/164

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over