12-56086799-G-A

Variant names:

• chr12-56086799-G-A
• rs877636
• NM_001982.4:c.547+143G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 44 publications found

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]

ERBB3 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.547+143G>A		intron_variant	Intron 4 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.370+143G>A		intron_variant	Intron 4 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.370+143G>A		intron_variant	Intron 4 of 27		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.547+143G>A		intron_variant	Intron 4 of 27	1	NM_001982.4	ENSP00000267101.4

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

African (AFR) AF: 0.415 AC: 8593 AN: 20698

American (AMR) AF: 0.795 AC: 31403 AN: 39478

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 12698 AN: 20416

East Asian (EAS) AF: 0.796 AC: 28335 AN: 35618

South Asian (SAS) AF: 0.767 AC: 53133 AN: 69314

European-Finnish (FIN) AF: 0.700 AC: 33484 AN: 47816

Middle Eastern (MID) AF: 0.745 AC: 2183 AN: 2932

European-Non Finnish (NFE) AF: 0.657 AC: 337570 AN: 513700

Other (OTH) AF: 0.667 AC: 25123 AN: 37680

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

African (AFR) AF: 0.417 AC: 17254 AN: 41332

American (AMR) AF: 0.723 AC: 11015 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2139 AN: 3470

East Asian (EAS) AF: 0.780 AC: 4028 AN: 5164

South Asian (SAS) AF: 0.773 AC: 3719 AN: 4810

European-Finnish (FIN) AF: 0.720 AC: 7600 AN: 10556

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45292 AN: 67910

Other (OTH) AF: 0.650 AC: 1362 AN: 2096

Alfa AF: 0.657 Hom.: 38846

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

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.6
DANN	Benign	0.59
PhyloP100		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs877636; hg19: chr12-56480583;