17-43209941-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005899.5(NBR1):​c.2768A>T​(p.His923Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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: not found (cov: 29)
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16258118).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005899.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBR1	NM_005899.5	MANE Select	c.2768A>T	p.His923Leu	missense	Exon 21 of 21	NP_005890.2
	NBR1	NM_031862.4		c.2768A>T	p.His923Leu	missense	Exon 21 of 21	NP_114068.1
	NBR1	NM_001291572.2		c.*27A>T		3_prime_UTR	Exon 18 of 18	NP_001278501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBR1	ENST00000590996.6	TSL:1 MANE Select	c.2768A>T	p.His923Leu	missense	Exon 21 of 21	ENSP00000466667.1
	NBR1	ENST00000341165.10	TSL:1	c.2768A>T	p.His923Leu	missense	Exon 21 of 21	ENSP00000343479.5
	NBR1	ENST00000955671.1		c.2822A>T	p.His941Leu	missense	Exon 21 of 21	ENSP00000625730.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.055	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Benign	0.69	T
Sift4G	Benign	0.78	T
Polyphen		0.93	P
Vest4		0.36
MutPred		0.38		Gain of helix (P = 0.1736)
MVP		0.58
ClinPred		0.45	T
GERP RS		5.9
Varity_R		0.26
gMVP		0.21

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

Other links and lift over

dbSNP: rs8482; hg19: chr17-41361960;