rs61752327

Variant names:

• chr14-31787811-T-C
• rs61752327
• NM_025152.3:c.545T>C

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.545T>C​(p.Val182Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00276 in 1,612,978 control chromosomes in the GnomAD database, including 10 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 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: NUBPL NM_025152.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7 O:1
• Conservation: PhyloP100: 6.85
• Publications: 15 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=0.027035683).
• BP6: Variant 14-31787811-T-C is Benign according to our data. Variant chr14-31787811-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214874.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00251 (382/152340) while in subpopulation NFE AF = 0.00414 (282/68034). AF 95% confidence interval is 0.00375. There are 0 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.545T>C	p.Val182Ala	missense	Exon 7 of 11	NP_079428.2	X5D2R5
	NUBPL	NM_001201573.2		c.257T>C	p.Val86Ala	missense	Exon 5 of 9	NP_001188502.1	B4DWB0
	NUBPL	NM_001201574.2		c.-5T>C		5_prime_UTR	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.545T>C	p.Val182Ala	missense	Exon 7 of 11	ENSP00000281081.7	Q8TB37-1
	NUBPL	ENST00000858673.1		c.545T>C	p.Val182Ala	missense	Exon 7 of 12	ENSP00000528732.1
	NUBPL	ENST00000858677.1		c.539T>C	p.Val180Ala	missense	Exon 7 of 11	ENSP00000528736.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00248 AC: 619 AN: 249272 AF XY: 0.00253

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00279 AC: 4068 AN: 1460638 Hom.: 10 Cov.: 29 AF XY: 0.00270 AC XY: 1965 AN XY: 726742

African (AFR) AF: 0.000329 AC: 11 AN: 33466

American (AMR) AF: 0.000962 AC: 43 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00305 AC: 163 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00320 AC: 3550 AN: 1110946

Other (OTH) AF: 0.00282 AC: 170 AN: 60330

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74490

African (AFR) AF: 0.000481 AC: 20 AN: 41578

American (AMR) AF: 0.00111 AC: 17 AN: 15304

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00414 AC: 282 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00356 Hom.: 2

Bravo AF: 0.00208

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.00451 AC: 37

ExAC AF: 0.00288 AC: 348

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 21 (1)
-	-	1	NUBPL-related disorder (1)
-	-	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.92	P
Vest4		0.60
MVP		0.72
MPC		0.39
ClinPred		0.066	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.81
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs61752327; hg19: chr14-32257017;