dbSNP rs118161496: NUBPL:c.815-27T>C (chr14-31850092-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 6P and 5B. PS3PP3PP5BS1_SupportingBS2

The NM_025152.3(NUBPL):c.815-27T>C variant causes a intron change. The variant allele was found at a frequency of 0.00373 in 1,571,878 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000251972: Expression studies of the c.815-27 T>C sequence change found that this variant impairs mRNA splicing resulting in a 80% decrease in complex I assembly and function (Tucker et al., 2012" and additional evidence is available in ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 19 hom. )

Consequence

NUBPL
NM_025152.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:6

Conservation

PhyloP100: 3.77

Publications

14 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 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

NUBPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000251972: Expression studies of the c.815-27 T>C sequence change found that this variant impairs mRNA splicing resulting in a 80% decrease in complex I assembly and function (Tucker et al., 2012; Wydro et al., 2013).; SCV000262906: 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).; SCV006079628: Functional studies of the c.815-27T>C variant resulted in lower expression of the NUBPL protein leading to an 80% decrease in complex I assembly and function (PMID: 22072591, 23828044, 29982452).; SCV001423626: "This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3]."; SCV006101083: "Fibroblasts from patients with this variant produces diminished residual complex I activity (PMID: 20818383)."

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 14-31850092-T-C is Pathogenic according to our data. Variant chr14-31850092-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50317.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00339 (516/152374) while in subpopulation NFE AF = 0.00442 (301/68042). AF 95% confidence interval is 0.00401. There are 3 homozygotes in GnomAd4. There are 271 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NUBPL	NM_025152.3	MANE Select	c.815-27T>C	intron	N/A	NP_079428.2	X5D2R5
NUBPL	NM_001201573.2		c.527-27T>C	intron	N/A	NP_001188502.1	B4DWB0
NUBPL	NM_001201574.2		c.266-27T>C	intron	N/A	NP_001188503.1	B3KSK2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.815-27T>C	intron	N/A	ENSP00000281081.7	Q8TB37-1
NUBPL	ENST00000858673.1		c.935-27T>C	intron	N/A	ENSP00000528732.1
NUBPL	ENST00000858677.1		c.809-27T>C	intron	N/A	ENSP00000528736.1

Frequencies

GnomAD3 genomes

AF:

0.00340

AC:

517

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00345

AC:

857

AN:

248676

AF XY:

0.00349

show subpopulations

Gnomad AFR exome

AF:

0.000777

Gnomad AMR exome

AF:

0.000726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.00442

Gnomad OTH exome

AF:

0.00513

GnomAD4 exome

AF:

0.00377

AC:

5351

AN:

1419504

Hom.:

Cov.:

AF XY:

0.00373

AC XY:

2645

AN XY:

709074

show subpopulations

African (AFR)

AF:

0.000459

AC:

AN:

32676

American (AMR)

AF:

0.000806

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00108

AC:

AN:

85298

European-Finnish (FIN)

AF:

0.0124

AC:

661

AN:

53348

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00407

AC:

4370

AN:

1073574

Other (OTH)

AF:

0.00286

AC:

169

AN:

58988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

268

536

804

1072

1340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.00339

AC:

516

AN:

152374

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

271

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41588

American (AMR)

AF:

0.00131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0149

AC:

158

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00442

AC:

301

AN:

68042

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00228

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial complex I deficiency, nuclear type 21 (9)

not provided (5)

Inborn genetic diseases (1)

Mitochondrial complex I deficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

3.8

BranchPoint Hunter

6.0

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.70

Position offset: -45

DS_AL_spliceai

0.71

Position offset: 27

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over