rs773620793

chr14-31599346-A-Cchr14-31599346-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_025152.3(NUBPL):c.349A>C(p.Met117Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M117I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NUBPL NM_025152.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.46

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-31599348-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 915894.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37317526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUBPL	NM_025152.3	c.349A>C	p.Met117Leu	missense_variant	4/11	ENST00000281081.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUBPL	ENST00000281081.12	c.349A>C	p.Met117Leu	missense_variant	4/11	1	NM_025152.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249314 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460508 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Benign	0.95
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.41	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.37
Sift	Benign	1.0	T;T
Sift4G	Benign	0.61	T;T
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.81		Loss of catalytic residue at V113 (P = 0.0436);.;
MVP		0.31
MPC		0.24
ClinPred		0.40	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.81

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: rs773620793; hg19: chr14-32068552;