7-151345361-G-T

Position:

• chr7-151345361-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001243351.2(NUB1):​c.12G>T​(p.Lys4Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0112 in 1,609,544 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (136 hom.)
• Consequence: NUB1 NM_001243351.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.60

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006970763).
• BP6: Variant 7-151345361-G-T is Benign according to our data. Variant chr7-151345361-G-T is described in ClinVar as [Benign]. Clinvar id is 774318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUB1	NM_001243351.2	c.12G>T	p.Lys4Asn	missense_variant	2/15	ENST00000568733.6	NP_001230280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUB1	ENST00000568733.6	c.12G>T	p.Lys4Asn	missense_variant	2/15	1	NM_001243351.2	ENSP00000454264.2

Frequencies

GnomAD3 genomes AF: 0.00756 AC: 1150 AN: 152114 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00805 AC: 1994 AN: 247654 Hom.: 9 AF XY: 0.00801 AC XY: 1077 AN XY: 134412

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00964

GnomAD4 exome AF: 0.0116 AC: 16906 AN: 1457312 Hom.: 136 Cov.: 28 AF XY: 0.0112 AC XY: 8156 AN XY: 725194

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00346

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00845

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152232 Hom.: 8 Cov.: 32 AF XY: 0.00769 AC XY: 572 AN XY: 74428

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0170

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0105 Hom.: 7

Bravo AF: 0.00640

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.000276 AC: 1

ESP6500EA AF: 0.0113 AC: 92

ExAC AF: 0.00749 AC: 905

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0115

EpiControl AF: 0.00951

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0067	T;T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.0070	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	.;.;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.21	N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.29	T;T;D;D
Polyphen		0.94	.;.;P;.
Vest4		0.54
MutPred		0.24		.;.;Loss of MoRF binding (P = 0.0224);Loss of MoRF binding (P = 0.0224);
MVP		0.50
MPC		0.50
ClinPred		0.019	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61734185; hg19: chr7-151042447; COSMIC: COSV99054280;