7-151349155-C-A

Position:

• chr7-151349155-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001243351.2(NUB1):​c.200C>A​(p.Ala67Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUB1 NM_001243351.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

Genes affected

NUB1 (HGNC:17623): (negative regulator of ubiquitin like proteins 1) This gene encodes a protein that functions as a negative regulator of NEDD8, a ubiquitin-like protein that conjugates with cullin family members in order to regulate vital biological events. The protein encoded by this gene regulates the NEDD8 conjugation system post-transcriptionally by recruiting NEDD8 and its conjugates to the proteasome for degradation. This protein interacts with the product of the AIPL1 gene, which is associated with Leber congenital amaurosis, an inherited retinopathy, and mutations in that gene can abolish interaction with this protein, which may contribute to the pathogenesis. This protein is also known to accumulate in Lewy bodies in Parkinson's disease and dementia with Lewy bodies, and in glial cytoplasmic inclusions in multiple system atrophy, with this abnormal accumulation being specific to alpha-synucleinopathy lesions. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUB1	NM_001243351.2	c.200C>A	p.Ala67Glu	missense_variant	3/15	ENST00000568733.6	NP_001230280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUB1	ENST00000568733.6	c.200C>A	p.Ala67Glu	missense_variant	3/15	1	NM_001243351.2	ENSP00000454264.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.272C>A (p.A91E) alteration is located in exon 3 (coding exon 3) of the NUB1 gene. This alteration results from a C to A substitution at nucleotide position 272, causing the alanine (A) at amino acid position 91 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.1	.;.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.90
MutPred		0.62		.;.;Gain of disorder (P = 0.0144);Gain of disorder (P = 0.0144);
MVP		0.81
MPC		1.0
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.80
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-151046241;