12-56080595-T-C

Variant names:

• chr12-56080595-T-C
• rs3741499
• NM_001982.4:c.82+213T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001982.4(ERBB3):​c.82+213T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 152,158 control chromosomes in the GnomAD database, including 32,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.65 (32740 hom., cov: 33)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.159
• Publications: 18 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-56080595-T-C is Benign according to our data. Variant chr12-56080595-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.764 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.82+213T>C		intron	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.82+213T>C		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.82+213T>C		intron	N/A	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000411731.6	TSL:1	c.82+213T>C		intron	N/A	ENSP00000415753.2	P21860-2
	ERBB3	ENST00000551242.5	TSL:1	n.82+213T>C		intron	N/A	ENSP00000447510.1	P21860-3

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99252 AN: 152040 Hom.: 32701 Cov.: 33

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.694

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.661

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.653 AC: 99342 AN: 152158 Hom.: 32740 Cov.: 33 AF XY: 0.660 AC XY: 49112 AN XY: 74380

African (AFR) AF: 0.568 AC: 23586 AN: 41514

American (AMR) AF: 0.733 AC: 11205 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2170 AN: 3472

East Asian (EAS) AF: 0.784 AC: 4054 AN: 5170

South Asian (SAS) AF: 0.771 AC: 3720 AN: 4824

European-Finnish (FIN) AF: 0.694 AC: 7363 AN: 10604

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45164 AN: 67970

Other (OTH) AF: 0.664 AC: 1401 AN: 2110

Alfa AF: 0.584 Hom.: 2989

Bravo AF: 0.649

Asia WGS AF: 0.802 AC: 2784 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.7
DANN	Benign	0.44
PhyloP100		-0.16
PromoterAI		0.026	Neutral
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: rs3741499; hg19: chr12-56474379;