17-43209941-A-G

Variant names:

• chr17-43209941-A-G
• rs8482
• NM_005899.5:c.2768A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005899.5(NBR1):​c.2768A>G​(p.His923Arg) variant causes a missense change. The variant allele was found at a frequency of 0.341 in 1,602,308 control chromosomes in the GnomAD database, including 95,394 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H923Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8094 hom., cov: 29)
  • Exomes 𝑓: 0.34 (87300 hom.)
• Consequence: NBR1 NM_005899.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.21
• Publications: 37 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016250908).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBR1	NM_005899.5	c.2768A>G	p.His923Arg	missense_variant	Exon 21 of 21	ENST00000590996.6	NP_005890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBR1	ENST00000590996.6	c.2768A>G	p.His923Arg	missense_variant	Exon 21 of 21	1	NM_005899.5	ENSP00000466667.1
NBR1	ENST00000341165.10	c.2768A>G	p.His923Arg	missense_variant	Exon 21 of 21	1		ENSP00000343479.5
NBR1	ENST00000542611.5	c.*27A>G		3_prime_UTR_variant	Exon 18 of 18	2		ENSP00000437545.1
NBR1	ENST00000589872.1	c.*298A>G		downstream_gene_variant		1		ENSP00000467816.1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 48449 AN: 150018 Hom.: 8090 Cov.: 29

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.362

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.356 AC: 83381 AN: 234204 AF XY: 0.364

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.372

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.343 AC: 498511 AN: 1452180 Hom.: 87300 Cov.: 38 AF XY: 0.348 AC XY: 251424 AN XY: 721860

African (AFR) AF: 0.241 AC: 8033 AN: 33348

American (AMR) AF: 0.322 AC: 13749 AN: 42734

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9504 AN: 25922

East Asian (EAS) AF: 0.352 AC: 13848 AN: 39392

South Asian (SAS) AF: 0.502 AC: 42667 AN: 85040

European-Finnish (FIN) AF: 0.397 AC: 21054 AN: 52992

Middle Eastern (MID) AF: 0.375 AC: 2146 AN: 5730

European-Non Finnish (NFE) AF: 0.331 AC: 366929 AN: 1107000

Other (OTH) AF: 0.343 AC: 20581 AN: 60022

GnomAD4 genome AF: 0.323 AC: 48477 AN: 150128 Hom.: 8094 Cov.: 29 AF XY: 0.329 AC XY: 24102 AN XY: 73152

African (AFR) AF: 0.244 AC: 9939 AN: 40652

American (AMR) AF: 0.336 AC: 5020 AN: 14956

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1243 AN: 3454

East Asian (EAS) AF: 0.371 AC: 1895 AN: 5114

South Asian (SAS) AF: 0.494 AC: 2357 AN: 4768

European-Finnish (FIN) AF: 0.410 AC: 4186 AN: 10210

Middle Eastern (MID) AF: 0.362 AC: 105 AN: 290

European-Non Finnish (NFE) AF: 0.336 AC: 22765 AN: 67692

Other (OTH) AF: 0.340 AC: 709 AN: 2086

Alfa AF: 0.328 Hom.: 17128

Bravo AF: 0.307

TwinsUK AF: 0.342 AC: 1269

ALSPAC AF: 0.340 AC: 1311

ESP6500AA AF: 0.248 AC: 777

ESP6500EA AF: 0.331 AC: 2371

ExAC AF: 0.344 AC: 41357

Asia WGS AF: 0.410 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.66	.;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.76	N;N
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.079
Sift	Benign	0.54	T;.
Sift4G	Benign	0.30	T;T
Polyphen		0.97	D;D
Vest4		0.073
ClinPred		0.029	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8482; hg19: chr17-41361960; COSMIC: COSV57831499; COSMIC: COSV57831499;