rs877636

Positions:

• chr12-56086799-G-A
• chr12-56086799-G-C
• chr12-56086799-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001982.4(ERBB3):​c.547+143G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 939,426 control chromosomes in the GnomAD database, including 212,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (29855 hom., cov: 29)
  • Exomes 𝑓: 0.68 (182626 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.830

Genes affected

ERBB3 (HGNC:3431): (erb-b2 receptor tyrosine kinase 3) This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-56086799-G-A is Benign according to our data. Variant chr12-56086799-G-A is described in ClinVar as [Benign]. Clinvar id is 1181926.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB3	NM_001982.4	c.547+143G>A		intron_variant		ENST00000267101.8
ERBB3	XM_047428500.1	c.370+143G>A		intron_variant
ERBB3	XM_047428501.1	c.370+143G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8	c.547+143G>A		intron_variant		1	NM_001982.4	P1

Frequencies

GnomAD3 genomes AF: 0.613 AC: 93016 AN: 151656 Hom.: 29824 Cov.: 29

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.647

GnomAD4 exome AF: 0.676 AC: 532522 AN: 787652 Hom.: 182626 AF XY: 0.681 AC XY: 281713 AN XY: 413726

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.796

Gnomad4 SAS exome AF: 0.767

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.657

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.613 AC: 93095 AN: 151774 Hom.: 29855 Cov.: 29 AF XY: 0.624 AC XY: 46293 AN XY: 74182

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.667

Gnomad4 OTH AF: 0.650

Alfa AF: 0.659 Hom.: 32237

Bravo AF: 0.601

Asia WGS AF: 0.803 AC: 2790 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.6
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs877636; hg19: chr12-56480583;