rs200401432

Positions:

chr14-31562125-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_025152.3(NUBPL):c.166G>A(p.Gly56Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G56E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NUBPL
NM_025152.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.85

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38876656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUBPL	NM_025152.3 linkuse as main transcript	c.166G>A	p.Gly56Arg	missense_variant	2/11	ENST00000281081.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUBPL	ENST00000281081.12 linkuse as main transcript	c.166G>A	p.Gly56Arg	missense_variant	2/11	1	NM_025152.3	P1	Q8TB37-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000141

AC:

AN:

248964

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135074

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000148

AC:

217

AN:

1461434

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000158

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000545

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.000141

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2020	Reported previously as a pathogenic variant in individuals with mitochondrial complex I deficiency who also harbored a splice variant on the same NUBPL allele (in cis) and another sequence change on the opposite NUBPL allele (Calvo et al., 2010; Tucker et al., 2012; Kevelam et al., 2013).; Functional analysis found this variant does not complex I assembly or function (Calvo et al., 2010; Kevelam et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32518176, 23553477, 20818383, 23828044, 22072591, 31787496) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 214885). This missense change has been observed in individual(s) with mitochondrial complex I deficiency. In all cases this variant has been reported to occur on the same chromosome (in cis) with c.815-27T>C. (PMID: 20818383, 22072591, 23553477, 32518176). This variant is present in population databases (rs200401432, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 56 of the NUBPL protein (p.Gly56Arg). -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2021

The c.166G>A (p.G56R) alteration is located in coding exon 2 of the NUBPL gene. This alteration results from a G to A substitution at nucleotide position 166, causing the glycine (G) at amino acid position 56 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the NUBPL p.G56R (c.166G>A) alteration was observed in 0.01% (41/280362) of total alleles studied (including 1 homozygote), with a frequency of 0.03% (39/128288) in the European (non-Finnish) subpopulation. The [c.166G>A (p.G56R); c.815-27T>C] complex allele has been reported in the homozygous state, compound heterozygous state, and confirmed in trans with a second pathogenic allele in multiple unrelated patients with mitochondrial encephalomyopathy (Calvo, 2010; Kevelam, 2013). Emerging evidence is suggestive that the NUBPL [c.166G>A (p.G56R); c.815-27T>C] complex allele is likely pathogenic when these alterations are in cis; however, the clinical significance of these alterations in isolation remains uncertain. The p.G56 amino acid is highly conserved in available vertebrate species. Functional analysis of cultured fibroblasts from a patient bearing the [c.166G>A (p.G56R); c.815-27T>C] complex allele in trans with a complex rearrangement, as well as a control patient who was heterozygous for only the c.815-27T>C alteration, demonstrated an aberrant RT-PCR pattern with three distinct transcripts: wild-type, a lengthened transcript resulting from a cryptic splice site which introduces an additional 72 bp and results in a frameshift (p.G272Vfs*11), as well as a truncated transcript generated due to exon 10 skipping resulting in a frameshift (p.D273Qfs*31) (Tucker, 2012). Analysis by qRT-PCR and Western blot showed that the heterozygous control with only the c.815-27T>C alteration had reduced mRNA expression (74%) and protein expression (59%) compared to wild type controls, and the patient with the [c.166G>A (p.G56R); c.815-27T>C] complex allele and complex rearrangement on the other allele had more significant reduction in mRNA expression (15%) and undetectable protein expression (Tucker, 2012). No defective function was identified when the protein with the G56R missense change was over-expressed (Tucker, 2012). The p.D273Qfs*31 transcript is completely non-functional in yeast assays (Wydro, 2013; Maclean, 2018). The p.G56R alteration is predicted to be tolerated by protein in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Mitochondrial complex 1 deficiency, nuclear type 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Aug 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.39

T;T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.9

D;D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.85

MutPred

0.31

.;Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);.;

MVP

0.57

MPC

0.60

ClinPred

0.43

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.80

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

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