12-56080024-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000683059.1(ERBB3):c.-96+90T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 530,504 control chromosomes in the GnomAD database, including 98,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26297 hom., cov: 32)
  • Exomes 𝑓: 0.61 (72473 hom.)
• Consequence: ERBB3 ENST00000683059.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-56080024-T-C is Benign according to our data. Variant chr12-56080024-T-C is described in ClinVar as [Benign]. Clinvar id is 1292949.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000549061.5	c.-134+90T>C		intron_variant		4
ERBB3	ENST00000549282.5	c.-105+90T>C		intron_variant		4
ERBB3	ENST00000643266.1	c.-96+3141T>C		intron_variant
ERBB3	ENST00000683059.1	c.-96+90T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88698 AN: 151886 Hom.: 26266 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.602

GnomAD4 exome AF: 0.613 AC: 231913 AN: 378498 Hom.: 72473 Cov.: 0 AF XY: 0.619 AC XY: 122527 AN XY: 197970

Gnomad4 AFR exome AF: 0.504

Gnomad4 AMR exome AF: 0.717

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.789

Gnomad4 SAS exome AF: 0.707

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.599

GnomAD4 genome AF: 0.584 AC: 88766 AN: 152006 Hom.: 26297 Cov.: 32 AF XY: 0.590 AC XY: 43848 AN XY: 74286

Gnomad4 AFR AF: 0.508

Gnomad4 AMR AF: 0.677

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.772

Gnomad4 SAS AF: 0.718

Gnomad4 FIN AF: 0.592

Gnomad4 NFE AF: 0.588

Gnomad4 OTH AF: 0.603

Alfa AF: 0.577 Hom.: 3593

Bravo AF: 0.585

Asia WGS AF: 0.743 AC: 2583 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

This variant is associated with the following publications: (PMID: 23060569) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.4
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs7297175; hg19: chr12-56473808;