14-31561439-C-T

Position:

• chr14-31561439-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025152.3(NUBPL):​c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00837 in 1,405,526 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (65 hom.)
• Consequence: NUBPL NM_025152.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0180

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-31561439-C-T is Benign according to our data. Variant chr14-31561439-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138567.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUBPL	NM_025152.3	c.-1C>T		5_prime_UTR_variant	1/11	ENST00000281081.12	NP_079428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUBPL	ENST00000281081.12	c.-1C>T		5_prime_UTR_variant	1/11	1	NM_025152.3	ENSP00000281081	P1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1023 AN: 152254 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00968

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00725 AC: 973 AN: 134240 Hom.: 3 AF XY: 0.00756 AC XY: 561 AN XY: 74202

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00351

Gnomad ASJ exome AF: 0.00473

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.00841

Gnomad OTH exome AF: 0.00503

GnomAD4 exome AF: 0.00857 AC: 10737 AN: 1253154 Hom.: 65 Cov.: 29 AF XY: 0.00860 AC XY: 5264 AN XY: 612016

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00445

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00275

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.00924

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00671 AC: 1023 AN: 152372 Hom.: 4 Cov.: 32 AF XY: 0.00711 AC XY: 530 AN XY: 74508

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.00969

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00531 Hom.: 3

Bravo AF: 0.00544

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NUBPL: BP4, BS2 -

Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.83

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

Other links and lift over

dbSNP: rs45468395; hg19: chr14-32030645;