rs705708

Positions:

• chr12-56095129-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000267101.8(ERBB3):​c.1860-128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 746,480 control chromosomes in the GnomAD database, including 66,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11880 hom., cov: 31)
  • Exomes 𝑓: 0.42 (54809 hom.)
• Consequence: ERBB3 ENST00000267101.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.650

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-56095129-G-A is Benign according to our data. Variant chr12-56095129-G-A is described in ClinVar as [Benign]. Clinvar id is 1237576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.1860-128G>A		intron_variant		ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.1683-128G>A		intron_variant			XP_047284456.1
ERBB3	XM_047428501.1	c.1683-128G>A		intron_variant			XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.1860-128G>A		intron_variant		1	NM_001982.4	ENSP00000267101	P1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58169 AN: 151772 Hom.: 11866 Cov.: 31

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.423 AC: 251776 AN: 594590 Hom.: 54809 AF XY: 0.419 AC XY: 134357 AN XY: 320334

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.404

Gnomad4 ASJ exome AF: 0.453

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.321

Gnomad4 FIN exome AF: 0.428

Gnomad4 NFE exome AF: 0.464

Gnomad4 OTH exome AF: 0.416

GnomAD4 genome AF: 0.383 AC: 58219 AN: 151890 Hom.: 11880 Cov.: 31 AF XY: 0.379 AC XY: 28150 AN XY: 74236

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.386

Alfa AF: 0.443 Hom.: 32289

Bravo AF: 0.378

Asia WGS AF: 0.331 AC: 1154 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.86
CADD	Benign	13
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs705708; hg19: chr12-56488913; COSMIC: COSV57262857; COSMIC: COSV57262857;