chr14-31561456-G-T

Variant names:

• chr14-31561456-G-T
• rs766023248
• NM_025152.3:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025152.3(NUBPL):​c.17G>T​(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,266,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: NUBPL NM_025152.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.790
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14055973).

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.17G>T	p.Arg6Leu	missense	Exon 1 of 11	NP_079428.2	X5D2R5
	NUBPL	NR_120408.2		n.53G>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.17G>T	p.Arg6Leu	missense	Exon 1 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 11	ENSP00000528736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1266996 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 620634

African (AFR) AF: 0.00 AC: 0 AN: 26348

American (AMR) AF: 0.00 AC: 0 AN: 23646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19254

East Asian (EAS) AF: 0.00 AC: 0 AN: 31320

South Asian (SAS) AF: 0.00 AC: 0 AN: 54334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5032

European-Non Finnish (NFE) AF: 0.00000198 AC: 2 AN: 1008932

Other (OTH) AF: 0.00 AC: 0 AN: 50790

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.79
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.36	B
Vest4		0.59
MutPred		0.51		Loss of MoRF binding (P = 0.0015)
MVP		0.53
MPC		0.28
ClinPred		0.84	D
GERP RS		0.44
PromoterAI		0.051	Neutral
Varity_R		0.12
gMVP		0.60
Mutation Taster		=98/2	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: rs766023248; hg19: chr14-32030662; COSMIC: COSV55273417; COSMIC: COSV55273417;