12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAA

Variant names:

• chr12-56100939-CAAAAAAAAA-C
• rs10536745
• NM_001982.4:c.3202-105_3202-97delAAAAAAAAA

Variant summary

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

The NM_001982.4(ERBB3):​c.3202-105_3202-97delAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 253,050 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: not found (cov: 0)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.561
• Publications: 0 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.3202-105_3202-97delAAAAAAAAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-105_3025-97delAAAAAAAAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-105_3025-97delAAAAAAAAA		intron_variant	Intron 26 of 27		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.3202-121_3202-113delAAAAAAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000356 AC: 9 AN: 253050 Hom.: 0 AF XY: 0.0000212 AC XY: 3 AN XY: 141250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.0000693 AC: 1 AN: 14436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7506

East Asian (EAS) AF: 0.0000924 AC: 1 AN: 10818

South Asian (SAS) AF: 0.00 AC: 0 AN: 43838

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: 0.0000342 AC: 5 AN: 146194

Other (OTH) AF: 0.0000823 AC: 1 AN: 12144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000006), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56

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;