12-56076841-C-T

Position:

• chr12-56076841-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000643266.1	c.-138C>T		5_prime_UTR_variant	1/2			ENSP00000495453

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.875

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 1.00

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

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.646

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.774

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.555

Alfa AF: 0.581 Hom.: 47701

Bravo AF: 0.493

Asia WGS AF: 0.729 AC: 2531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.7
DANN	Benign	0.54

Splicing

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

Publications

LitVar

Other links and lift over

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