17-43189619-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005899.5(NBR1):c.512A>G(p.Glu171Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBR1 NM_005899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

NBR1 (HGNC:6746): (NBR1 autophagy cargo receptor) The protein encoded by this gene was originally identified as an ovarian tumor antigen monitored in ovarian cancer. The encoded protein contains a B-box/coiled-coil motif, which is present in many genes with transformation potential. It functions as a specific autophagy receptor for the selective autophagic degradation of peroxisomes by forming intracellular inclusions with ubiquitylated autophagic substrates. This gene is located on a region of chromosome 17q21.1 that is in close proximity to the BRCA1 tumor suppressor gene. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBR1	NM_005899.5	c.512A>G	p.Glu171Gly	missense_variant	8/21	ENST00000590996.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBR1	ENST00000590996.6	c.512A>G	p.Glu171Gly	missense_variant	8/21	1	NM_005899.5	P1
NBR1	ENST00000341165.10	c.512A>G	p.Glu171Gly	missense_variant	8/21	1		P1
NBR1	ENST00000589872.1	c.512A>G	p.Glu171Gly	missense_variant	8/21	1
NBR1	ENST00000542611.5	c.449A>G	p.Glu150Gly	missense_variant	7/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 15, 2022

The c.512A>G (p.E171G) alteration is located in exon 8 (coding exon 7) of the NBR1 gene. This alteration results from a A to G substitution at nucleotide position 512, causing the glutamic acid (E) at amino acid position 171 to be replaced by a glycine (G). 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	Benign	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.1	D;D;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.60
MutPred		0.30		Loss of ubiquitination at K172 (P = 0.0426);.;Loss of ubiquitination at K172 (P = 0.0426);Loss of ubiquitination at K172 (P = 0.0426);
MVP		0.69
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr17-41341636;