12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAA

Variant names:

• chr12-56100939-CAA-C
• rs10536745
• NM_001982.4:c.3202-98_3202-97delAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001982.4(ERBB3):​c.3202-98_3202-97delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 283,306 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 0.0071 (0 hom., cov: 0)
  • Exomes 𝑓: 0.14 (1 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.561
• 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: 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00713 (361/50642) while in subpopulation AFR AF = 0.0142 (156/10994). AF 95% confidence interval is 0.0124. There are 0 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.3202-98_3202-97delAA		intron	N/A	NP_001973.2	P21860-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.3202-121_3202-120delAA		intron	N/A	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000550070.6	TSL:1	c.1123-121_1123-120delAA		intron	N/A	ENSP00000448946.2	F8VYK4
	ERBB3	ENST00000551242.5	TSL:1	n.*57-121_*57-120delAA		intron	N/A	ENSP00000447510.1	P21860-3

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 361 AN: 50650 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00527

Gnomad ASJ AF: 0.00366

Gnomad EAS AF: 0.00326

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.00799

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00727

GnomAD4 exome AF: 0.139 AC: 32342 AN: 232664 Hom.: 1 AF XY: 0.140 AC XY: 18169 AN XY: 130034

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

African (AFR) AF: 0.118 AC: 650 AN: 5508

American (AMR) AF: 0.140 AC: 1846 AN: 13198

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 855 AN: 7078

East Asian (EAS) AF: 0.158 AC: 1590 AN: 10064

South Asian (SAS) AF: 0.141 AC: 5667 AN: 40064

European-Finnish (FIN) AF: 0.140 AC: 1446 AN: 10322

Middle Eastern (MID) AF: 0.165 AC: 128 AN: 774

European-Non Finnish (NFE) AF: 0.138 AC: 18494 AN: 134444

Other (OTH) AF: 0.149 AC: 1666 AN: 11212

⚠️ 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: 0.00713 AC: 361 AN: 50642 Hom.: 0 Cov.: 0 AF XY: 0.00722 AC XY: 160 AN XY: 22154

African (AFR) AF: 0.0142 AC: 156 AN: 10994

American (AMR) AF: 0.00526 AC: 20 AN: 3802

Ashkenazi Jewish (ASJ) AF: 0.00366 AC: 6 AN: 1640

East Asian (EAS) AF: 0.00326 AC: 5 AN: 1534

South Asian (SAS) AF: 0.0120 AC: 12 AN: 996

European-Finnish (FIN) AF: 0.00799 AC: 5 AN: 626

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

European-Non Finnish (NFE) AF: 0.00510 AC: 152 AN: 29816

Other (OTH) AF: 0.00720 AC: 5 AN: 694

Alfa AF: 0.00 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

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: rs10536745; hg19: chr12-56494723;