12-56088396-T-G

Variant names:

• chr12-56088396-T-G
• rs2292239
• NM_001982.4:c.875-147T>G

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.875-147T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 854,640 control chromosomes in the GnomAD database, including 202,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33255 hom., cov: 31)
  • Exomes 𝑓: 0.69 (169169 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.125
• Publications: 192 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=-0.85).
• BP6: Variant 12-56088396-T-G is Benign according to our data. Variant chr12-56088396-T-G is described in ClinVar as Benign. ClinVar VariationId is 1250075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.875-147T>G		intron	N/A	NP_001973.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.875-147T>G		intron	N/A	ENSP00000267101.4
	ERBB3	ENST00000551242.5	TSL:1	n.875-147T>G		intron	N/A	ENSP00000447510.1
	ERBB3	ENST00000415288.6	TSL:2	c.698-147T>G		intron	N/A	ENSP00000408340.2

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100007 AN: 151864 Hom.: 33231 Cov.: 31

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.667

GnomAD4 exome AF: 0.691 AC: 485630 AN: 702658 Hom.: 169169 AF XY: 0.694 AC XY: 261817 AN XY: 377194

African (AFR) AF: 0.583 AC: 11052 AN: 18944

American (AMR) AF: 0.805 AC: 34460 AN: 42828

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 13184 AN: 21110

East Asian (EAS) AF: 0.798 AC: 28980 AN: 36332

South Asian (SAS) AF: 0.767 AC: 53850 AN: 70236

European-Finnish (FIN) AF: 0.695 AC: 31731 AN: 45638

Middle Eastern (MID) AF: 0.755 AC: 2252 AN: 2984

European-Non Finnish (NFE) AF: 0.667 AC: 286082 AN: 429166

Other (OTH) AF: 0.679 AC: 24039 AN: 35420

GnomAD4 genome AF: 0.658 AC: 100075 AN: 151982 Hom.: 33255 Cov.: 31 AF XY: 0.667 AC XY: 49524 AN XY: 74286

African (AFR) AF: 0.575 AC: 23817 AN: 41420

American (AMR) AF: 0.738 AC: 11256 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2134 AN: 3468

East Asian (EAS) AF: 0.782 AC: 4044 AN: 5174

South Asian (SAS) AF: 0.773 AC: 3718 AN: 4808

European-Finnish (FIN) AF: 0.720 AC: 7621 AN: 10582

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45395 AN: 67966

Other (OTH) AF: 0.666 AC: 1402 AN: 2104

Alfa AF: 0.666 Hom.: 132431

Bravo AF: 0.654

Asia WGS AF: 0.766 AC: 2660 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.089
DANN	Benign	0.66
PhyloP100		-0.13
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: rs2292239; hg19: chr12-56482180;