rs2271189

Variant names:

• chr12-56101207-G-A
• rs2271189
• NM_001982.4:c.3348G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-56101207-G-A
• chr12-56101207-G-C
• chr12-56101207-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001982.4(ERBB3):​c.3348G>A​(p.Arg1116Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,613,462 control chromosomes in the GnomAD database, including 116,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8334 hom., cov: 30)
  • Exomes 𝑓: 0.38 (108235 hom.)
• Consequence: ERBB3 NM_001982.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.554
• Publications: 47 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

ENSG00000257411 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 12-56101207-G-A is Benign according to our data. Variant chr12-56101207-G-A is described in ClinVar as Benign. ClinVar VariationId is 1248586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.554 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.3348G>A	p.Arg1116Arg	synonymous_variant	Exon 27 of 28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3171G>A	p.Arg1057Arg	synonymous_variant	Exon 27 of 28		XP_047284456.1
ERBB3	XM_047428501.1	c.3171G>A	p.Arg1057Arg	synonymous_variant	Exon 27 of 28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.3348G>A	p.Arg1116Arg	synonymous_variant	Exon 27 of 28	1	NM_001982.4	ENSP00000267101.4
ENSG00000257411	ENST00000548861.2	c.-124G>A		upstream_gene_variant		5		ENSP00000449770.3

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46725 AN: 151578 Hom.: 8330 Cov.: 30

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.347 AC: 87056 AN: 251170 AF XY: 0.347

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.361

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.380 AC: 555279 AN: 1461766 Hom.: 108235 Cov.: 57 AF XY: 0.377 AC XY: 274491 AN XY: 727198

African (AFR) AF: 0.117 AC: 3905 AN: 33466

American (AMR) AF: 0.356 AC: 15916 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9636 AN: 26136

East Asian (EAS) AF: 0.321 AC: 12724 AN: 39700

South Asian (SAS) AF: 0.259 AC: 22315 AN: 86256

European-Finnish (FIN) AF: 0.387 AC: 20698 AN: 53418

Middle Eastern (MID) AF: 0.261 AC: 1503 AN: 5768

European-Non Finnish (NFE) AF: 0.402 AC: 446861 AN: 1111926

Other (OTH) AF: 0.360 AC: 21721 AN: 60394

GnomAD4 genome AF: 0.308 AC: 46746 AN: 151696 Hom.: 8334 Cov.: 30 AF XY: 0.306 AC XY: 22654 AN XY: 74134

African (AFR) AF: 0.124 AC: 5108 AN: 41330

American (AMR) AF: 0.340 AC: 5184 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1320 AN: 3468

East Asian (EAS) AF: 0.312 AC: 1604 AN: 5148

South Asian (SAS) AF: 0.250 AC: 1203 AN: 4810

European-Finnish (FIN) AF: 0.375 AC: 3950 AN: 10526

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.400 AC: 27167 AN: 67850

Other (OTH) AF: 0.314 AC: 661 AN: 2104

Alfa AF: 0.355 Hom.: 16274

Bravo AF: 0.300

Asia WGS AF: 0.274 AC: 954 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.376

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Lethal congenital contracture syndrome 2 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Visceral neuropathy, familial Benign:1

Jul 30, 2021

Genome-Nilou Lab

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	-0.53
CADD	Benign	1.8
DANN	Benign	0.86
PhyloP100		-0.55
PromoterAI		-0.0015	Neutral
Mutation Taster		=99/1	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: rs2271189; hg19: chr12-56494991; COSMIC: COSV57251880; COSMIC: COSV57251880;