12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAA

Variant names:

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

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_3202-97dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 298,222 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 0.015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0084 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.015 (747/49646) while in subpopulation AFR AF = 0.0174 (185/10662). AF 95% confidence interval is 0.0153. There are 0 homozygotes in GnomAd4. There are 298 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.3202-98_3202-97dupAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-98_3025-97dupAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-98_3025-97dupAA		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_3202-121insAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 747 AN: 49652 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.0207

Gnomad AMR AF: 0.00689

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.00596

Gnomad FIN AF: 0.00639

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00737

GnomAD4 exome AF: 0.00844 AC: 2099 AN: 248576 Hom.: 0 AF XY: 0.00831 AC XY: 1153 AN XY: 138794

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

African (AFR) AF: 0.0145 AC: 85 AN: 5880

American (AMR) AF: 0.00717 AC: 102 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00688 AC: 51 AN: 7408

East Asian (EAS) AF: 0.00648 AC: 69 AN: 10648

South Asian (SAS) AF: 0.00651 AC: 281 AN: 43178

European-Finnish (FIN) AF: 0.00651 AC: 72 AN: 11054

Middle Eastern (MID) AF: 0.00856 AC: 7 AN: 818

European-Non Finnish (NFE) AF: 0.00935 AC: 1341 AN: 143424

Other (OTH) AF: 0.00762 AC: 91 AN: 11938

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0150 AC: 747 AN: 49646 Hom.: 0 Cov.: 0 AF XY: 0.0137 AC XY: 298 AN XY: 21742

African (AFR) AF: 0.0174 AC: 185 AN: 10662

American (AMR) AF: 0.00687 AC: 26 AN: 3784

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 26 AN: 1602

East Asian (EAS) AF: 0.0106 AC: 16 AN: 1514

South Asian (SAS) AF: 0.00602 AC: 6 AN: 996

European-Finnish (FIN) AF: 0.00639 AC: 4 AN: 626

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

European-Non Finnish (NFE) AF: 0.0161 AC: 470 AN: 29272

Other (OTH) AF: 0.00731 AC: 5 AN: 684

Alfa AF: 0.0116 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;