12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAA

Variant names:

• chr12-56100939-C-CAAA
• rs10536745
• NM_001982.4:c.3202-99_3202-97dupAAA

Variant summary

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

The NM_001982.4(ERBB3):​c.3202-99_3202-97dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 302,634 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0110
• 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.3202-99_3202-97dupAAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-99_3025-97dupAAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-99_3025-97dupAAA		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.3202-122_3202-121insAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 70 AN: 50614 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00427

Gnomad AMR AF: 0.000790

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.000651

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00161

Gnomad OTH AF: 0.00290

GnomAD4 exome AF: 0.00143 AC: 360 AN: 252028 Hom.: 1 AF XY: 0.00137 AC XY: 193 AN XY: 140672

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

African (AFR) AF: 0.00133 AC: 8 AN: 6028

American (AMR) AF: 0.00104 AC: 15 AN: 14386

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 10 AN: 7486

East Asian (EAS) AF: 0.00149 AC: 16 AN: 10760

South Asian (SAS) AF: 0.000870 AC: 38 AN: 43680

European-Finnish (FIN) AF: 0.00134 AC: 15 AN: 11180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 832

European-Non Finnish (NFE) AF: 0.00162 AC: 236 AN: 145570

Other (OTH) AF: 0.00182 AC: 22 AN: 12106

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00138 AC: 70 AN: 50606 Hom.: 0 Cov.: 0 AF XY: 0.00122 AC XY: 27 AN XY: 22134

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

African (AFR) AF: 0.00109 AC: 12 AN: 11000

American (AMR) AF: 0.000788 AC: 3 AN: 3806

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 2 AN: 1640

East Asian (EAS) AF: 0.000652 AC: 1 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: 0.00161 AC: 48 AN: 29768

Other (OTH) AF: 0.00287 AC: 2 AN: 696

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000145839), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00347 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.011

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;