chr12-56100939-CAAAAAAAAAAAA-C

Variant names:

• chr12-56100939-CAAAAAAAAAAAA-C
• rs10536745
• NM_001982.4:c.3202-108_3202-97delAAAAAAAAAAAA

Variant summary

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

The NM_001982.4(ERBB3):​c.3202-108_3202-97delAAAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000948 in 303,734 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• 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 amr. GnomAd4 allele frequency = 0.0014 (71/50668) while in subpopulation AMR AF = 0.00552 (21/3804). AF 95% confidence interval is 0.0037. There are 1 homozygotes in GnomAd4. There are 33 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.3202-108_3202-97delAAAAAAAAAAAA		intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3025-108_3025-97delAAAAAAAAAAAA		intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1	c.3025-108_3025-97delAAAAAAAAAAAA		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_3202-110delAAAAAAAAAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 71 AN: 50676 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00553

Gnomad ASJ AF: 0.00426

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00398

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00290

GnomAD4 exome AF: 0.000857 AC: 217 AN: 253066 Hom.: 0 AF XY: 0.000842 AC XY: 119 AN XY: 141262

African (AFR) AF: 0.00115 AC: 7 AN: 6070

American (AMR) AF: 0.00111 AC: 16 AN: 14440

Ashkenazi Jewish (ASJ) AF: 0.00280 AC: 21 AN: 7506

East Asian (EAS) AF: 0.00 AC: 0 AN: 10818

South Asian (SAS) AF: 0.000456 AC: 20 AN: 43836

European-Finnish (FIN) AF: 0.0000892 AC: 1 AN: 11206

Middle Eastern (MID) AF: 0.00119 AC: 1 AN: 838

European-Non Finnish (NFE) AF: 0.000917 AC: 134 AN: 146206

Other (OTH) AF: 0.00140 AC: 17 AN: 12146

GnomAD4 genome AF: 0.00140 AC: 71 AN: 50668 Hom.: 1 Cov.: 0 AF XY: 0.00149 AC XY: 33 AN XY: 22170

African (AFR) AF: 0.000454 AC: 5 AN: 11016

American (AMR) AF: 0.00552 AC: 21 AN: 3804

Ashkenazi Jewish (ASJ) AF: 0.00426 AC: 7 AN: 1644

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

South Asian (SAS) AF: 0.00402 AC: 4 AN: 996

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

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

European-Non Finnish (NFE) AF: 0.00107 AC: 32 AN: 29812

Other (OTH) AF: 0.00287 AC: 2 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		1.6
Mutation Taster		=100/0	polymorphism

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;