12-56079996-G-A

Position:

• chr12-56079996-G-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+62G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0296 in 493,424 control chromosomes in the GnomAD database, including 1,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (1446 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (336 hom.)
• Consequence: ERBB3 ENST00000683059.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.471

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=-0.7).
• BP6: Variant 12-56079996-G-A is Benign according to our data. Variant chr12-56079996-G-A is described in ClinVar as [Benign]. Clinvar id is 1235907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 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	ENST00000549061.5	c.-134+62G>A		intron_variant		4		ENSP00000449138
ERBB3	ENST00000549282.5	c.-105+62G>A		intron_variant		4		ENSP00000448636
ERBB3	ENST00000643266.1	c.-96+3113G>A		intron_variant				ENSP00000495453
ERBB3	ENST00000683059.1	c.-96+62G>A		intron_variant				ENSP00000507402

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11403 AN: 152128 Hom.: 1440 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0417

GnomAD4 exome AF: 0.00934 AC: 3188 AN: 341178 Hom.: 336 Cov.: 0 AF XY: 0.00780 AC XY: 1384 AN XY: 177378

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.00546

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000532

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000534

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0750 AC: 11424 AN: 152246 Hom.: 1446 Cov.: 32 AF XY: 0.0720 AC XY: 5357 AN XY: 74454

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0587 Hom.: 109

Bravo AF: 0.0851

Asia WGS AF: 0.0120 AC: 41 AN: 3478

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	clinical testing	GeneDx	Oct 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.83

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: rs115699610; hg19: chr12-56473780;