17-43189613-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005899.5(NBR1):c.506C>T(p.Thr169Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: NBR1 NM_005899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3705538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBR1	NM_005899.5	c.506C>T	p.Thr169Met	missense_variant	8/21	ENST00000590996.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBR1	ENST00000590996.6	c.506C>T	p.Thr169Met	missense_variant	8/21	1	NM_005899.5	P1
NBR1	ENST00000341165.10	c.506C>T	p.Thr169Met	missense_variant	8/21	1		P1
NBR1	ENST00000589872.1	c.506C>T	p.Thr169Met	missense_variant	8/21	1
NBR1	ENST00000542611.5	c.443C>T	p.Thr148Met	missense_variant	7/18	2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249184 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135196

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727092

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jun 27, 2022

The c.506C>T (p.T169M) alteration is located in exon 8 (coding exon 7) of the NBR1 gene. This alteration results from a C to T substitution at nucleotide position 506, causing the threonine (T) at amino acid position 169 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N;N;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D;D;.;.
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.54
MutPred		0.27		Gain of catalytic residue at V165 (P = 0.0143);.;Gain of catalytic residue at V165 (P = 0.0143);Gain of catalytic residue at V165 (P = 0.0143);
MVP		0.71
ClinPred		0.42	T
GERP RS		5.9
Varity_R		0.16
gMVP		0.32

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: rs764800232; hg19: chr17-41341630;