rs11558436

Variant names:

• chr14-31787859-A-C
• rs11558436
• NM_025152.3:c.593A>C

Your query was ambiguous. Multiple possible variants found:

• chr14-31787859-A-C
• chr14-31787859-A-G

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.593A>C​(p.Asn198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00518 in 1,607,730 control chromosomes in the GnomAD database, including 28 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 0.0047 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (24 hom.)
• Consequence: NUBPL NM_025152.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 6.23
• Publications: 10 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 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 21

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011787027).
• BP6: Variant 14-31787859-A-C is Benign according to our data. Variant chr14-31787859-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214875.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00466 (710/152344) while in subpopulation NFE AF = 0.00713 (485/68040). AF 95% confidence interval is 0.0066. There are 4 homozygotes in GnomAd4. There are 346 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.593A>C	p.Asn198Thr	missense	Exon 7 of 11	NP_079428.2	X5D2R5
	NUBPL	NM_001201573.2		c.305A>C	p.Asn102Thr	missense	Exon 5 of 9	NP_001188502.1	B4DWB0
	NUBPL	NM_001201574.2		c.44A>C	p.Asn15Thr	missense	Exon 2 of 6	NP_001188503.1	B3KSK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.593A>C	p.Asn198Thr	missense	Exon 7 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.593A>C	p.Asn198Thr	missense	Exon 7 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.587A>C	p.Asn196Thr	missense	Exon 7 of 11	ENSP00000528736.1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 710 AN: 152226 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00417 AC: 1039 AN: 249130 AF XY: 0.00421

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00645

Gnomad NFE exome AF: 0.00628

Gnomad OTH exome AF: 0.00380

GnomAD4 exome AF: 0.00524 AC: 7622 AN: 1455386 Hom.: 24 Cov.: 28 AF XY: 0.00521 AC XY: 3772 AN XY: 724626

African (AFR) AF: 0.000869 AC: 29 AN: 33360

American (AMR) AF: 0.00197 AC: 88 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00293 AC: 252 AN: 86114

European-Finnish (FIN) AF: 0.00704 AC: 376 AN: 53378

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5708

European-Non Finnish (NFE) AF: 0.00595 AC: 6586 AN: 1106270

Other (OTH) AF: 0.00469 AC: 282 AN: 60146

GnomAD4 genome AF: 0.00466 AC: 710 AN: 152344 Hom.: 4 Cov.: 32 AF XY: 0.00464 AC XY: 346 AN XY: 74490

African (AFR) AF: 0.000818 AC: 34 AN: 41584

American (AMR) AF: 0.00366 AC: 56 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00650 AC: 69 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00713 AC: 485 AN: 68040

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00543 Hom.: 9

Bravo AF: 0.00390

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000810 AC: 3

ESP6500EA AF: 0.00636 AC: 52

ExAC AF: 0.00438 AC: 529

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Inborn genetic diseases (1)
-	-	1	Mitochondrial complex I deficiency (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 21 (1)
-	-	1	NUBPL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N
PhyloP100		6.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.21	T
Sift4G	Benign	0.36	T
Polyphen		0.89	P
Vest4		0.69
MVP		0.53
MPC		0.37
ClinPred		0.0073	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.73
Mutation Taster		=84/16	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: rs11558436; hg19: chr14-32257065; COSMIC: COSV105149127; COSMIC: COSV105149127;