12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAA

Variant names:

• chr12-56100939-CAAAAAAAAAA-C
• rs10536745
• NM_001982.4:c.3202-106_3202-97delAAAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001982.4(ERBB3):​c.3202-106_3202-97delAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 303,720 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3202-106_3202-97delAAAAAAAAAA		intron	N/A	NP_001973.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.3202-121_3202-112delAAAAAAAAAA		intron	N/A	ENSP00000267101.4
	ERBB3	ENST00000550070.6	TSL:1	c.1123-121_1123-112delAAAAAAAAAA		intron	N/A	ENSP00000448946.2
	ERBB3	ENST00000551242.5	TSL:1	n.*57-121_*57-112delAAAAAAAAAA		intron	N/A	ENSP00000447510.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 2 AN: 50668 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000335

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 3 AN: 253060 Hom.: 0 AF XY: 0.0000142 AC XY: 2 AN XY: 141258

African (AFR) AF: 0.00 AC: 0 AN: 6070

American (AMR) AF: 0.000139 AC: 2 AN: 14440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7504

East Asian (EAS) AF: 0.00 AC: 0 AN: 10818

South Asian (SAS) AF: 0.00 AC: 0 AN: 43836

European-Finnish (FIN) AF: 0.0000892 AC: 1 AN: 11206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 838

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 146202

Other (OTH) AF: 0.00 AC: 0 AN: 12146

GnomAD4 genome AF: 0.0000395 AC: 2 AN: 50660 Hom.: 0 Cov.: 0 AF XY: 0.0000451 AC XY: 1 AN XY: 22166

African (AFR) AF: 0.00 AC: 0 AN: 11016

American (AMR) AF: 0.000263 AC: 1 AN: 3804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1642

East Asian (EAS) AF: 0.00 AC: 0 AN: 1534

South Asian (SAS) AF: 0.00 AC: 0 AN: 996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 72

European-Non Finnish (NFE) AF: 0.0000336 AC: 1 AN: 29806

Other (OTH) AF: 0.00 AC: 0 AN: 696

Alfa AF: 0.00 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10536745; hg19: chr12-56494723;