12-56088396-T-G

Position:

• chr12-56088396-T-G

Variant summary

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

The NM_001982.4(ERBB3):​c.875-147T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 854,640 control chromosomes in the GnomAD database, including 202,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33255 hom., cov: 31)
  • Exomes 𝑓: 0.69 (169169 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.125

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=-0.85).
• BP6: Variant 12-56088396-T-G is Benign according to our data. Variant chr12-56088396-T-G is described in ClinVar as [Benign]. Clinvar id is 1250075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.875-147T>G		intron_variant		ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.698-147T>G		intron_variant			XP_047284456.1
ERBB3	XM_047428501.1	c.698-147T>G		intron_variant			XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.875-147T>G		intron_variant		1	NM_001982.4	ENSP00000267101	P1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100007 AN: 151864 Hom.: 33231 Cov.: 31

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.667

GnomAD4 exome AF: 0.691 AC: 485630 AN: 702658 Hom.: 169169 AF XY: 0.694 AC XY: 261817 AN XY: 377194

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.805

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.798

Gnomad4 SAS exome AF: 0.767

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.679

GnomAD4 genome AF: 0.658 AC: 100075 AN: 151982 Hom.: 33255 Cov.: 31 AF XY: 0.667 AC XY: 49524 AN XY: 74286

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.738

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.782

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.668

Gnomad4 OTH AF: 0.666

Alfa AF: 0.670 Hom.: 61709

Bravo AF: 0.654

Asia WGS AF: 0.766 AC: 2660 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	Nov 11, 2018	- -
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	-0.85
CADD	Benign	0.089
DANN	Benign	0.66

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: rs2292239; hg19: chr12-56482180;