chr12-56084874-A-C

Variant names:

• chr12-56084874-A-C
• rs7971751
• NM_001982.4:c.235-121A>C

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.235-121A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,485,504 control chromosomes in the GnomAD database, including 257,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22372 hom., cov: 30)
  • Exomes 𝑓: 0.59 (235042 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-56084874-A-C is Benign according to our data. Variant chr12-56084874-A-C is described in ClinVar as Benign. ClinVar VariationId is 1221690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 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.235-121A>C		intron	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.235-121A>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.235-121A>C		intron	N/A	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000411731.6	TSL:1	c.235-121A>C		intron	N/A	ENSP00000415753.2	P21860-2
	ERBB3	ENST00000551242.5	TSL:1	n.235-121A>C		intron	N/A	ENSP00000447510.1	P21860-3

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78302 AN: 151882 Hom.: 22356 Cov.: 30

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.564

GnomAD4 exome AF: 0.588 AC: 783738 AN: 1333504 Hom.: 235042 AF XY: 0.593 AC XY: 392273 AN XY: 661812

African (AFR) AF: 0.248 AC: 7324 AN: 29584

American (AMR) AF: 0.742 AC: 25311 AN: 34092

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 13446 AN: 24344

East Asian (EAS) AF: 0.789 AC: 29102 AN: 36904

South Asian (SAS) AF: 0.714 AC: 55798 AN: 78156

European-Finnish (FIN) AF: 0.594 AC: 23318 AN: 39238

Middle Eastern (MID) AF: 0.698 AC: 3719 AN: 5330

European-Non Finnish (NFE) AF: 0.576 AC: 592852 AN: 1030006

Other (OTH) AF: 0.589 AC: 32868 AN: 55850

GnomAD4 genome AF: 0.515 AC: 78349 AN: 152000 Hom.: 22372 Cov.: 30 AF XY: 0.526 AC XY: 39063 AN XY: 74294

African (AFR) AF: 0.258 AC: 10689 AN: 41456

American (AMR) AF: 0.654 AC: 9975 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1881 AN: 3472

East Asian (EAS) AF: 0.773 AC: 4008 AN: 5188

South Asian (SAS) AF: 0.720 AC: 3456 AN: 4802

European-Finnish (FIN) AF: 0.620 AC: 6545 AN: 10554

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

European-Non Finnish (NFE) AF: 0.589 AC: 40028 AN: 67966

Other (OTH) AF: 0.565 AC: 1190 AN: 2106

Alfa AF: 0.557 Hom.: 5310

Bravo AF: 0.505

Asia WGS AF: 0.740 AC: 2569 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.7
DANN	Benign	0.60
PhyloP100		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: rs7971751; hg19: chr12-56478658;