12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chr12-56100939-CAAAAA-C
• rs10536745
• NM_001982.4:c.3202-101_3202-97delAAAAA

Variant summary

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

The NM_001982.4(ERBB3):​c.3202-101_3202-97delAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 299,378 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 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0056 (0 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: 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 = 0.00111 (56/50656) while in subpopulation AFR AF = 0.0049 (54/11014). AF 95% confidence interval is 0.00386. There are 0 homozygotes in GnomAd4. There are 19 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.3202-101_3202-97delAAAAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-101_3025-97delAAAAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-101_3025-97delAAAAA		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_3202-117delAAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 56 AN: 50664 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00491

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: 0.0000335

Gnomad OTH AF: 0.00145

GnomAD4 exome AF: 0.00558 AC: 1389 AN: 248722 Hom.: 0 AF XY: 0.00540 AC XY: 750 AN XY: 138844

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

African (AFR) AF: 0.00637 AC: 38 AN: 5968

American (AMR) AF: 0.00682 AC: 97 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00525 AC: 39 AN: 7422

East Asian (EAS) AF: 0.00964 AC: 102 AN: 10576

South Asian (SAS) AF: 0.00332 AC: 143 AN: 43054

European-Finnish (FIN) AF: 0.00681 AC: 75 AN: 11016

Middle Eastern (MID) AF: 0.0109 AC: 9 AN: 822

European-Non Finnish (NFE) AF: 0.00562 AC: 808 AN: 143676

Other (OTH) AF: 0.00652 AC: 78 AN: 11960

⚠️ 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: 0.00111 AC: 56 AN: 50656 Hom.: 0 Cov.: 0 AF XY: 0.000857 AC XY: 19 AN XY: 22162

African (AFR) AF: 0.00490 AC: 54 AN: 11014

American (AMR) AF: 0.00 AC: 0 AN: 3804

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1534

South Asian (SAS) AF: 0.00 AC: 0 AN: 996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 624

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

European-Non Finnish (NFE) AF: 0.0000336 AC: 1 AN: 29806

Other (OTH) AF: 0.00144 AC: 1 AN: 696

Alfa AF: 0.00 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56

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;