12-56084898-A-G

Variant names:

• chr12-56084898-A-G
• rs73338402
• NM_001982.4:c.235-97A>G

Variant summary

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

The NM_001982.4(ERBB3):​c.235-97A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,579,672 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (130 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (86 hom.)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.991
• Publications: 1 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=-0.88).
• BP6: Variant 12-56084898-A-G is Benign according to our data. Variant chr12-56084898-A-G is described in ClinVar as Benign. ClinVar VariationId is 1225126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0726 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001982.4. 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.235-97A>G		intron	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.235-97A>G		intron	N/A	NP_001005915.1	P21860-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.235-97A>G		intron	N/A	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000411731.6	TSL:1	c.235-97A>G		intron	N/A	ENSP00000415753.2	P21860-2
	ERBB3	ENST00000551242.5	TSL:1	n.235-97A>G		intron	N/A	ENSP00000447510.1	P21860-3

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3256 AN: 152104 Hom.: 130 Cov.: 31

Gnomad AFR AF: 0.0747

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.00210 AC: 3003 AN: 1427450 Hom.: 86 AF XY: 0.00190 AC XY: 1350 AN XY: 709494

African (AFR) AF: 0.0748 AC: 2430 AN: 32508

American (AMR) AF: 0.00428 AC: 177 AN: 41346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.00 AC: 0 AN: 39172

South Asian (SAS) AF: 0.000263 AC: 22 AN: 83618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46302

Middle Eastern (MID) AF: 0.00281 AC: 16 AN: 5684

European-Non Finnish (NFE) AF: 0.0000622 AC: 68 AN: 1093904

Other (OTH) AF: 0.00489 AC: 290 AN: 59296

GnomAD4 genome AF: 0.0215 AC: 3268 AN: 152222 Hom.: 130 Cov.: 31 AF XY: 0.0209 AC XY: 1558 AN XY: 74444

African (AFR) AF: 0.0748 AC: 3105 AN: 41518

American (AMR) AF: 0.00733 AC: 112 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68010

Other (OTH) AF: 0.0176 AC: 37 AN: 2108

Alfa AF: 0.0171 Hom.: 5

Bravo AF: 0.0232

Asia WGS AF: 0.00491 AC: 18 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	-0.88
CADD	Benign	5.5
DANN	Benign	0.34
PhyloP100		0.99
Mutation Taster		=100/0	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: rs73338402; hg19: chr12-56478682; COSMIC: COSV104386515;