rs2271188

chr12-56101239-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001982.4(ERBB3):c.3380G>A(p.Arg1127His) variant causes a missense change. The variant allele was found at a frequency of 0.000502 in 1,614,040 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00071 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.51

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ERBB3
• BP4: Computational evidence support a benign effect (MetaRNN=0.008962393).
• BP6: Variant 12-56101239-G-A is Benign according to our data. Variant chr12-56101239-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00071 (108/152156) while in subpopulation EAS AF= 0.0116 (60/5168). AF 95% confidence interval is 0.00926. There are 4 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB3	NM_001982.4	c.3380G>A	p.Arg1127His	missense_variant	27/28	ENST00000267101.8
ERBB3	XM_047428500.1	c.3203G>A	p.Arg1068His	missense_variant	27/28
ERBB3	XM_047428501.1	c.3203G>A	p.Arg1068His	missense_variant	27/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8	c.3380G>A	p.Arg1127His	missense_variant	27/28	1	NM_001982.4	P1

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 152038 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000744 AC: 187 AN: 251366 Hom.: 0 AF XY: 0.000699 AC XY: 95 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00745

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000480 AC: 702 AN: 1461884 Hom.: 7 Cov.: 33 AF XY: 0.000518 AC XY: 377 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0120

Gnomad4 SAS exome AF: 0.000985

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000710 AC: 108 AN: 152156 Hom.: 4 Cov.: 30 AF XY: 0.000672 AC XY: 50 AN XY: 74402

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00138 Hom.: 30

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	This variant is associated with the following publications: (PMID: 23856252) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

ERBB3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T;T;T;T
MetaRNN	Benign	0.0090	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.6	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N;N;.;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.029	D;D;.;D;D
Sift4G	Benign	0.19	T;T;D;T;D
Polyphen		0.99	D;D;.;.;D
Vest4		0.17
MVP		0.95
MPC		1.1
ClinPred		0.091	T
GERP RS		6.2
Varity_R		0.041
gMVP		0.30

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: rs2271188; hg19: chr12-56495023; COSMIC: COSV57252825; COSMIC: COSV57252825;