rs2292238

Positions:

• chr12-56100038-A-C

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.3129+9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,612,632 control chromosomes in the GnomAD database, including 122,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9193 hom., cov: 32)
  • Exomes 𝑓: 0.39 (113517 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.18

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=-0.82).
• BP6: Variant 12-56100038-A-C is Benign according to our data. Variant chr12-56100038-A-C is described in ClinVar as [Benign]. Clinvar id is 1226099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56100038-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB3	NM_001982.4	c.3129+9A>C		intron_variant		ENST00000267101.8
ERBB3	XM_047428500.1	c.2952+9A>C		intron_variant
ERBB3	XM_047428501.1	c.2952+9A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8	c.3129+9A>C		intron_variant		1	NM_001982.4	P1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50818 AN: 151994 Hom.: 9179 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.346

GnomAD3 exomes AF: 0.365 AC: 91819 AN: 251364 Hom.: 17251 AF XY: 0.365 AC XY: 49627 AN XY: 135864

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.290

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.391 AC: 570683 AN: 1460520 Hom.: 113517 Cov.: 35 AF XY: 0.389 AC XY: 282694 AN XY: 726604

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.406

Gnomad4 EAS exome AF: 0.342

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.334 AC: 50874 AN: 152112 Hom.: 9193 Cov.: 32 AF XY: 0.332 AC XY: 24718 AN XY: 74366

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.342

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.379

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.345

Alfa AF: 0.374 Hom.: 6263

Bravo AF: 0.329

Asia WGS AF: 0.342 AC: 1189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal congenital contracture syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Visceral neuropathy, familial Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.70

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: rs2292238; hg19: chr12-56493822; COSMIC: COSV57256344; COSMIC: COSV57256344;