chr12-56100939-CAAAA-C

Variant names:

• chr12-56100939-CAAAA-C
• rs10536745
• NM_001982.4:c.3202-100_3202-97delAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001982.4(ERBB3):​c.3202-100_3202-97delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 291,110 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 0.00043 (0 hom., cov: 0)
  • Exomes 𝑓: 0.017 (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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.3202-100_3202-97delAAAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-100_3025-97delAAAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-100_3025-97delAAAA		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_3202-118delAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 22 AN: 50666 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

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: 0.000134

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0175 AC: 4202 AN: 240444 Hom.: 0 AF XY: 0.0173 AC XY: 2317 AN XY: 134236

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

African (AFR) AF: 0.0147 AC: 86 AN: 5848

American (AMR) AF: 0.0154 AC: 211 AN: 13708

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 130 AN: 7258

East Asian (EAS) AF: 0.0301 AC: 308 AN: 10244

South Asian (SAS) AF: 0.0129 AC: 532 AN: 41284

European-Finnish (FIN) AF: 0.0175 AC: 186 AN: 10600

Middle Eastern (MID) AF: 0.0163 AC: 13 AN: 800

European-Non Finnish (NFE) AF: 0.0179 AC: 2496 AN: 139146

Other (OTH) AF: 0.0208 AC: 240 AN: 11556

⚠️ 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: 0.000434 AC: 22 AN: 50666 Hom.: 0 Cov.: 0 AF XY: 0.000496 AC XY: 11 AN XY: 22168

African (AFR) AF: 0.00154 AC: 17 AN: 11008

American (AMR) AF: 0.000263 AC: 1 AN: 3796

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1536

South Asian (SAS) AF: 0.00 AC: 0 AN: 1006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 82

European-Non Finnish (NFE) AF: 0.000134 AC: 4 AN: 29812

Other (OTH) AF: 0.00 AC: 0 AN: 690

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
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;