17-43186284-A-C

Position:

• chr17-43186284-A-C

Variant summary

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

The ENST00000590996.6(NBR1):​c.242A>C​(p.Gln81Pro) variant causes a missense change. 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 ENST00000590996.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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	Protein	UniProt
NBR1	NM_005899.5	c.242A>C	p.Gln81Pro	missense_variant	6/21	ENST00000590996.6	NP_005890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBR1	ENST00000590996.6	c.242A>C	p.Gln81Pro	missense_variant	6/21	1	NM_005899.5	ENSP00000466667	P1
NBR1	ENST00000341165.10	c.242A>C	p.Gln81Pro	missense_variant	6/21	1		ENSP00000343479	P1
NBR1	ENST00000589872.1	c.242A>C	p.Gln81Pro	missense_variant	6/21	1		ENSP00000467816
NBR1	ENST00000542611.5	c.179A>C	p.Gln60Pro	missense_variant	5/18	2		ENSP00000437545

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 15, 2023

The c.242A>C (p.Q81P) alteration is located in exon 6 (coding exon 5) of the NBR1 gene. This alteration results from a A to C substitution at nucleotide position 242, causing the glutamine (Q) at amino acid position 81 to be replaced by a proline (P). 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	0.70
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T;.
Eigen	Benign	0.034
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N;.;N;N
MutationTaster	Benign	0.86	D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.033	D;D;.;.
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.55	P;B;P;P
Vest4		0.59
MutPred		0.67		Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.53
ClinPred		0.76	D
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.73
gMVP		0.74

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: chr17-41338301;