12-56076841-C-T

Variant names:

• chr12-56076841-C-T
• rs11171739
• ENST00000643266.1:c.-138C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000643266.1(ERBB3):​c.-138C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 150,900 control chromosomes in the GnomAD database, including 21,507 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (21479 hom., cov: 26)
  • Exomes 𝑓: 0.64 (28 hom.)
• Consequence: ERBB3 ENST00000643266.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710
• Publications: 153 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643266.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000643266.1		c.-138C>T		5_prime_UTR	Exon 1 of 2	ENSP00000495453.1	A0A2R8Y6T4
	ERBB3	ENST00000643518.1		n.-71C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75694 AN: 150664 Hom.: 21476 Cov.: 26

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.644 AC: 76 AN: 118 Hom.: 28 Cov.: 0 AF XY: 0.683 AC XY: 56 AN XY: 82

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.500 AC: 2 AN: 4

South Asian (SAS) AF: 0.875 AC: 7 AN: 8

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.670 AC: 59 AN: 88

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.502 AC: 75703 AN: 150782 Hom.: 21479 Cov.: 26 AF XY: 0.511 AC XY: 37590 AN XY: 73544

African (AFR) AF: 0.224 AC: 9202 AN: 41048

American (AMR) AF: 0.646 AC: 9747 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1863 AN: 3468

East Asian (EAS) AF: 0.774 AC: 3909 AN: 5052

South Asian (SAS) AF: 0.717 AC: 3424 AN: 4776

European-Finnish (FIN) AF: 0.591 AC: 6081 AN: 10296

Middle Eastern (MID) AF: 0.664 AC: 194 AN: 292

European-Non Finnish (NFE) AF: 0.586 AC: 39744 AN: 67772

Other (OTH) AF: 0.555 AC: 1160 AN: 2090

Alfa AF: 0.572 Hom.: 98062

Bravo AF: 0.493

Asia WGS AF: 0.729 AC: 2531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.7
DANN	Benign	0.54
PhyloP100		0.071
PromoterAI		-0.016	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11171739; hg19: chr12-56470625; COSMIC: COSV57257946;