12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001982.4(ERBB3):​c.3202-97delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 249,700 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (911 hom., cov: 0)
  • Exomes 𝑓: 0.18 (6 hom.)
  • Failed GnomAD Quality Control
• 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.

• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.391 AC: 20454 AN: 52302 Hom.: 915 Cov.: 0

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.524

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.406

GnomAD4 exome AF: 0.182 AC: 45349 AN: 249700 Hom.: 6 AF XY: 0.181 AC XY: 25174 AN XY: 139428

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

African (AFR) AF: 0.152 AC: 900 AN: 5940

American (AMR) AF: 0.169 AC: 2413 AN: 14254

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 1205 AN: 7392

East Asian (EAS) AF: 0.201 AC: 2148 AN: 10676

South Asian (SAS) AF: 0.171 AC: 7393 AN: 43282

European-Finnish (FIN) AF: 0.193 AC: 2142 AN: 11082

Middle Eastern (MID) AF: 0.180 AC: 149 AN: 828

European-Non Finnish (NFE) AF: 0.185 AC: 26728 AN: 144274

Other (OTH) AF: 0.190 AC: 2271 AN: 11972

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.391 AC: 20447 AN: 52298 Hom.: 911 Cov.: 0 AF XY: 0.391 AC XY: 8950 AN XY: 22894

African (AFR) AF: 0.300 AC: 3360 AN: 11184

American (AMR) AF: 0.423 AC: 1655 AN: 3910

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 703 AN: 1716

East Asian (EAS) AF: 0.446 AC: 719 AN: 1612

South Asian (SAS) AF: 0.486 AC: 500 AN: 1028

European-Finnish (FIN) AF: 0.409 AC: 259 AN: 634

Middle Eastern (MID) AF: 0.526 AC: 40 AN: 76

European-Non Finnish (NFE) AF: 0.412 AC: 12739 AN: 30914

Other (OTH) AF: 0.404 AC: 290 AN: 718

Alfa AF: 0.103 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.011
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;