12-56079996-G-A

Variant names:

• chr12-56079996-G-A
• rs115699610
• ENST00000926495.1:c.-102+62G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000549282.5(ERBB3):​c.-105+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 ENST00000549282.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.471
• Publications: 2 publications found

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]

ERBB3 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000549282.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.-305G>A		upstream_gene	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.-305G>A		upstream_gene	N/A	NP_001005915.1	P21860-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000926495.1		c.-102+62G>A		intron	N/A	ENSP00000596554.1
	ERBB3	ENST00000683059.1		c.-96+62G>A		intron	N/A	ENSP00000507402.1	P21860-4
	ERBB3	ENST00000549282.5	TSL:4	c.-105+62G>A		intron	N/A	ENSP00000448636.1	F8VRL0

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

African (AFR) AF: 0.255 AC: 2352 AN: 9226

American (AMR) AF: 0.0175 AC: 240 AN: 13738

Ashkenazi Jewish (ASJ) AF: 0.00546 AC: 61 AN: 11168

East Asian (EAS) AF: 0.00 AC: 0 AN: 22352

South Asian (SAS) AF: 0.000532 AC: 20 AN: 37612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20992

Middle Eastern (MID) AF: 0.00867 AC: 13 AN: 1500

European-Non Finnish (NFE) AF: 0.000534 AC: 109 AN: 204100

Other (OTH) AF: 0.0192 AC: 393 AN: 20490

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

African (AFR) AF: 0.262 AC: 10851 AN: 41488

American (AMR) AF: 0.0260 AC: 398 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68034

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0677 Hom.: 134

Bravo AF: 0.0851

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		0.47
PromoterAI		-0.025	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs115699610; hg19: chr12-56473780;