12-56084218-A-C

Variant names:

• chr12-56084218-A-C
• rs10876870
• NM_001982.4:c.234+316A>C

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.234+316A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,892 control chromosomes in the GnomAD database, including 22,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.52 (22344 hom., cov: 30)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.115
• Publications: 24 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 12-56084218-A-C is Benign according to our data. Variant chr12-56084218-A-C is described in ClinVar as Benign. ClinVar VariationId is 1286166.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.234+316A>C		intron	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.234+316A>C		intron	N/A	NP_001005915.1	P21860-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.234+316A>C		intron	N/A	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000411731.6	TSL:1	c.234+316A>C		intron	N/A	ENSP00000415753.2	P21860-2
	ERBB3	ENST00000551242.5	TSL:1	n.234+316A>C		intron	N/A	ENSP00000447510.1	P21860-3

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78230 AN: 151774 Hom.: 22328 Cov.: 30

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.565

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.515 AC: 78277 AN: 151892 Hom.: 22344 Cov.: 30 AF XY: 0.525 AC XY: 38995 AN XY: 74210

African (AFR) AF: 0.258 AC: 10679 AN: 41404

American (AMR) AF: 0.654 AC: 9969 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1879 AN: 3470

East Asian (EAS) AF: 0.773 AC: 3989 AN: 5162

South Asian (SAS) AF: 0.720 AC: 3461 AN: 4810

European-Finnish (FIN) AF: 0.618 AC: 6519 AN: 10556

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 40010 AN: 67922

Other (OTH) AF: 0.566 AC: 1195 AN: 2112

Alfa AF: 0.542 Hom.: 5313

Bravo AF: 0.505

Asia WGS AF: 0.739 AC: 2569 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.9
DANN	Benign	0.79
PhyloP100		0.12
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: rs10876870; hg19: chr12-56478002;