NM_001982.4:c.234+8A>T

Variant names:

• chr12-56083910-A-T
• rs2271194
• NM_001982.4:c.234+8A>T

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.234+8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,612,718 control chromosomes in the GnomAD database, including 283,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23400 hom., cov: 31)
  • Exomes 𝑓: 0.59 (260096 hom.)
• Consequence: ERBB3 NM_001982.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002307
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.44
• Publications: 62 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 12-56083910-A-T is Benign according to our data. Variant chr12-56083910-A-T is described in ClinVar as Benign. ClinVar VariationId is 1255390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 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.234+8A>T		splice_region intron	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.234+8A>T		splice_region 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.234+8A>T		splice_region intron	N/A	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000411731.6	TSL:1	c.234+8A>T		splice_region intron	N/A	ENSP00000415753.2	P21860-2
	ERBB3	ENST00000551242.5	TSL:1	n.234+8A>T		splice_region intron	N/A	ENSP00000447510.1	P21860-3

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81553 AN: 151770 Hom.: 23374 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.685

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.583

GnomAD2 exomes AF: 0.627 AC: 157568 AN: 251466 AF XY: 0.631

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.784

Gnomad FIN exome AF: 0.611

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.626

GnomAD4 exome AF: 0.592 AC: 864467 AN: 1460832 Hom.: 260096 Cov.: 39 AF XY: 0.596 AC XY: 433344 AN XY: 726744

African (AFR) AF: 0.321 AC: 10743 AN: 33464

American (AMR) AF: 0.755 AC: 33757 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 14441 AN: 26128

East Asian (EAS) AF: 0.793 AC: 31483 AN: 39690

South Asian (SAS) AF: 0.714 AC: 61562 AN: 86232

European-Finnish (FIN) AF: 0.600 AC: 32038 AN: 53396

Middle Eastern (MID) AF: 0.701 AC: 4033 AN: 5752

European-Non Finnish (NFE) AF: 0.576 AC: 640487 AN: 1111094

Other (OTH) AF: 0.595 AC: 35923 AN: 60358

GnomAD4 genome AF: 0.537 AC: 81617 AN: 151886 Hom.: 23400 Cov.: 31 AF XY: 0.547 AC XY: 40595 AN XY: 74206

African (AFR) AF: 0.333 AC: 13770 AN: 41404

American (AMR) AF: 0.662 AC: 10105 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1881 AN: 3470

East Asian (EAS) AF: 0.779 AC: 4031 AN: 5172

South Asian (SAS) AF: 0.720 AC: 3466 AN: 4814

European-Finnish (FIN) AF: 0.619 AC: 6529 AN: 10548

Middle Eastern (MID) AF: 0.675 AC: 197 AN: 292

European-Non Finnish (NFE) AF: 0.589 AC: 40022 AN: 67914

Other (OTH) AF: 0.587 AC: 1236 AN: 2106

Alfa AF: 0.571 Hom.: 8111

Bravo AF: 0.528

Asia WGS AF: 0.771 AC: 2680 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Lethal congenital contracture syndrome 2 (1)
-	-	1	Visceral neuropathy, familial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.065
DANN	Benign	0.46
PhyloP100		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs2271194; hg19: chr12-56477694; COSMIC: COSV57265950;