12-56080106-T-A

Position:

• chr12-56080106-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000683059.1(ERBB3):​c.-96+172T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 511,096 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: ERBB3 ENST00000683059.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-56080106-T-A is Benign according to our data. Variant chr12-56080106-T-A is described in ClinVar as [Benign]. Clinvar id is 1283687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001005915.1			upstream_gene_variant			NP_001005915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000549061.5	c.-134+172T>A		intron_variant		4		ENSP00000449138
ERBB3	ENST00000549282.5	c.-104-91T>A		intron_variant		4		ENSP00000448636
ERBB3	ENST00000643266.1	c.-96+3223T>A		intron_variant				ENSP00000495453

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2799 AN: 150738 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00529

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.0000970

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.0160

GnomAD4 exome AF: 0.00412 AC: 1483 AN: 360240 Hom.: 21 Cov.: 2 AF XY: 0.00391 AC XY: 748 AN XY: 191086

Gnomad4 AFR exome AF: 0.0747

Gnomad4 AMR exome AF: 0.00602

Gnomad4 ASJ exome AF: 0.000775

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.000992

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00804

GnomAD4 genome AF: 0.0187 AC: 2815 AN: 150856 Hom.: 94 Cov.: 32 AF XY: 0.0184 AC XY: 1353 AN XY: 73702

Gnomad4 AFR AF: 0.0647

Gnomad4 AMR AF: 0.00528

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.0000970

Gnomad4 NFE AF: 0.000414

Gnomad4 OTH AF: 0.0159

Alfa AF: 0.0113 Hom.: 4

Bravo AF: 0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.55

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: rs74094518; hg19: chr12-56473890; COSMIC: COSV57246140; COSMIC: COSV57246140;