rs705708

Variant names:

• chr12-56095129-G-A
• rs705708
• NM_001982.4:c.1860-128G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001982.4(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 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.650
• Publications: 43 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 -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 VariationId 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 rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.1860-128G>A		intron_variant	Intron 15 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.1683-128G>A		intron_variant	Intron 15 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.1683-128G>A		intron_variant	Intron 15 of 27		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.1860-128G>A		intron_variant	Intron 15 of 27	1	NM_001982.4	ENSP00000267101.4

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

African (AFR) AF: 0.242 AC: 4005 AN: 16552

American (AMR) AF: 0.404 AC: 14498 AN: 35886

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 8997 AN: 19874

East Asian (EAS) AF: 0.303 AC: 9958 AN: 32874

South Asian (SAS) AF: 0.321 AC: 20603 AN: 64126

European-Finnish (FIN) AF: 0.428 AC: 20336 AN: 47530

Middle Eastern (MID) AF: 0.323 AC: 1251 AN: 3868

European-Non Finnish (NFE) AF: 0.464 AC: 159054 AN: 342452

Other (OTH) AF: 0.416 AC: 13074 AN: 31428

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

African (AFR) AF: 0.247 AC: 10230 AN: 41398

American (AMR) AF: 0.399 AC: 6089 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1633 AN: 3472

East Asian (EAS) AF: 0.287 AC: 1482 AN: 5172

South Asian (SAS) AF: 0.317 AC: 1527 AN: 4810

European-Finnish (FIN) AF: 0.418 AC: 4411 AN: 10562

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31397 AN: 67908

Other (OTH) AF: 0.386 AC: 814 AN: 2108

Alfa AF: 0.436 Hom.: 67347

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.86
CADD	Benign	13
DANN	Benign	0.59
PhyloP100		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs705708; hg19: chr12-56488913; COSMIC: COSV57262857; COSMIC: COSV57262857;