NM_025152.3:c.-1C>T

Variant names:

• chr14-31561439-C-T
• rs45468395
• NM_025152.3:c.-1C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 138567.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00671 (1023/152372) while in subpopulation NFE AF = 0.00969 (659/68040). AF 95% confidence interval is 0.00907. There are 4 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	NM_025152.3	MANE Select	c.-1C>T		5_prime_UTR	Exon 1 of 11	NP_079428.2	X5D2R5
	NUBPL	NR_120408.2		n.36C>T		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.-1C>T		5_prime_UTR	Exon 1 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.-1C>T		5_prime_UTR	Exon 1 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.-1C>T		5_prime_UTR	Exon 1 of 11	ENSP00000528736.1

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

GnomAD2 exomes AF: 0.00725 AC: 973 AN: 134240 AF XY: 0.00756

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 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

African (AFR) AF: 0.00119 AC: 31 AN: 26138

American (AMR) AF: 0.00400 AC: 90 AN: 22502

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 83 AN: 18668

East Asian (EAS) AF: 0.00 AC: 0 AN: 31066

South Asian (SAS) AF: 0.00275 AC: 142 AN: 51656

European-Finnish (FIN) AF: 0.0166 AC: 774 AN: 46702

Middle Eastern (MID) AF: 0.00342 AC: 17 AN: 4976

European-Non Finnish (NFE) AF: 0.00924 AC: 9254 AN: 1001218

Other (OTH) AF: 0.00689 AC: 346 AN: 50228

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

African (AFR) AF: 0.00149 AC: 62 AN: 41596

American (AMR) AF: 0.00307 AC: 47 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 68040

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00747 Hom.: 12

Bravo AF: 0.00544

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		-0.018
PromoterAI		-0.055	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs45468395; hg19: chr14-32030645;