17-43186311-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005899.5(NBR1):c.269A>G(p.Asp90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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: 1.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06920448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBR1	NM_005899.5	c.269A>G	p.Asp90Gly	missense_variant	6/21	ENST00000590996.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBR1	ENST00000590996.6	c.269A>G	p.Asp90Gly	missense_variant	6/21	1	NM_005899.5	P1
NBR1	ENST00000341165.10	c.269A>G	p.Asp90Gly	missense_variant	6/21	1		P1
NBR1	ENST00000589872.1	c.269A>G	p.Asp90Gly	missense_variant	6/21	1
NBR1	ENST00000542611.5	c.206A>G	p.Asp69Gly	missense_variant	5/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 02, 2022

The c.269A>G (p.D90G) alteration is located in exon 6 (coding exon 5) of the NBR1 gene. This alteration results from a A to G substitution at nucleotide position 269, causing the aspartic acid (D) at amino acid position 90 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	0.070
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.57
DEOGEN2	Benign	0.015	T;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.069	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.30	N;N;.;.
REVEL	Benign	0.073
Sift	Benign	0.29	T;T;.;.
Sift4G	Benign	0.61	T;T;T;T
Polyphen		0.020	B;B;B;B
Vest4		0.061
MutPred		0.27		Loss of catalytic residue at D90 (P = 0.0056);.;Loss of catalytic residue at D90 (P = 0.0056);Loss of catalytic residue at D90 (P = 0.0056);
MVP		0.36
ClinPred		0.098	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.064
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr17-41338328;