12-56100939-CAAAAAAAAAAAAAAAA-CAAAAA

Variant names:

• chr12-56100939-CAAAAAAAAAAA-C
• rs10536745
• NM_001982.4:c.3202-107_3202-97delAAAAAAAAAAA

Variant summary

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

The NM_001982.4(ERBB3):​c.3202-107_3202-97delAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000955 in 303,730 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 0.00011 (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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.3202-107_3202-97delAAAAAAAAAAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-107_3025-97delAAAAAAAAAAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-107_3025-97delAAAAAAAAAAA		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_3202-111delAAAAAAAAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 2 AN: 50670 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 27 AN: 253060 Hom.: 0 AF XY: 0.000120 AC XY: 17 AN XY: 141262

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

American (AMR) AF: 0.00 AC: 0 AN: 14440

Ashkenazi Jewish (ASJ) AF: 0.000133 AC: 1 AN: 7506

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

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

European-Finnish (FIN) AF: 0.00107 AC: 12 AN: 11206

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

European-Non Finnish (NFE) AF: 0.0000958 AC: 14 AN: 146198

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

GnomAD4 genome AF: 0.0000395 AC: 2 AN: 50670 Hom.: 0 Cov.: 0 AF XY: 0.0000451 AC XY: 1 AN XY: 22168

African (AFR) AF: 0.000182 AC: 2 AN: 11012

American (AMR) AF: 0.00 AC: 0 AN: 3796

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1536

South Asian (SAS) AF: 0.00 AC: 0 AN: 1006

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 82

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 29812

Other (OTH) AF: 0.00 AC: 0 AN: 690

Alfa AF: 0.00 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;