rs567437692

Variant names:

• chr14-31561441-T-C
• rs567437692
• NM_025152.3:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 2.09
• 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: 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.

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.2T>C	p.Met1?	start_lost	Exon 1 of 11	NP_079428.2	X5D2R5
	NUBPL	NR_120408.2		n.38T>C		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.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENSP00000528736.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152088 Hom.: 0 Cov.: 32

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: 14 AN: 135226 AF XY: 0.000107

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: 41 AN: 1250180 Hom.: 0 Cov.: 29 AF XY: 0.0000377 AC XY: 23 AN XY: 610852

African (AFR) AF: 0.00 AC: 0 AN: 26080

American (AMR) AF: 0.0000887 AC: 2 AN: 22544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18700

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

South Asian (SAS) AF: 0.000485 AC: 25 AN: 51520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4976

European-Non Finnish (NFE) AF: 0.00000601 AC: 6 AN: 998466

Other (OTH) AF: 0.000160 AC: 8 AN: 50142

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000342 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000913 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Mitochondrial complex I deficiency, nuclear type 21 (2)
1	-	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial oxidative phosphorylation disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.0090	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.59	T
PhyloP100		2.1
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.85
MutPred		0.92		Loss of helix (P = 0.0104)
MVP		0.71
ClinPred		0.98	D
GERP RS		5.3
PromoterAI		-0.13	Neutral
Varity_R		0.94
gMVP		0.66
Mutation Taster		=36/164	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs567437692; hg19: chr14-32030647;