12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAA

Variant names:

• chr12-56100939-C-CA
• rs10536745
• NM_001982.4:c.3202-97dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001982.4(ERBB3):​c.3202-97dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0471 in 291,986 control chromosomes in the GnomAD database, including 69 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.072 (69 hom., cov: 0)
  • Exomes 𝑓: 0.042 (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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.078 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0716 AC: 3561 AN: 49710 Hom.: 69 Cov.: 0

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.0744

GnomAD4 exome AF: 0.0421 AC: 10203 AN: 242284 Hom.: 0 AF XY: 0.0413 AC XY: 5587 AN XY: 135434

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

African (AFR) AF: 0.0708 AC: 405 AN: 5722

American (AMR) AF: 0.0359 AC: 497 AN: 13842

Ashkenazi Jewish (ASJ) AF: 0.0402 AC: 293 AN: 7286

East Asian (EAS) AF: 0.0339 AC: 356 AN: 10502

South Asian (SAS) AF: 0.0316 AC: 1327 AN: 42040

European-Finnish (FIN) AF: 0.0414 AC: 446 AN: 10780

Middle Eastern (MID) AF: 0.0388 AC: 31 AN: 798

European-Non Finnish (NFE) AF: 0.0452 AC: 6317 AN: 139698

Other (OTH) AF: 0.0457 AC: 531 AN: 11616

⚠️ 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: 0.0716 AC: 3559 AN: 49702 Hom.: 69 Cov.: 0 AF XY: 0.0683 AC XY: 1488 AN XY: 21784

African (AFR) AF: 0.0649 AC: 696 AN: 10728

American (AMR) AF: 0.0485 AC: 183 AN: 3770

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 105 AN: 1612

East Asian (EAS) AF: 0.0423 AC: 64 AN: 1512

South Asian (SAS) AF: 0.0364 AC: 36 AN: 990

European-Finnish (FIN) AF: 0.0273 AC: 17 AN: 622

Middle Eastern (MID) AF: 0.0143 AC: 1 AN: 70

European-Non Finnish (NFE) AF: 0.0807 AC: 2363 AN: 29264

Other (OTH) AF: 0.0737 AC: 50 AN: 678

Alfa AF: 0.0343 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.011

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;