rs773123

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001982.4(ERBB3):c.3355A>T(p.Ser1119Cys) variant causes a missense change. The variant allele was found at a frequency of 0.106 in 1,613,498 control chromosomes in the GnomAD database, including 9,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.095 ( 727 hom., cov: 30)

Exomes 𝑓: 0.11 ( 9029 hom. )

Consequence

ERBB3
NM_001982.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.35

Variant links:

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 links:

ENSG00000257411 (HGNC:):

ENSG00000257411 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the ERBB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.3904 (below the threshold of 3.09). Trascript score misZ: 3.2897 (above the threshold of 3.09). GenCC associations: The gene is linked to Hirschsprung disease, lethal congenital contracture syndrome 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019624531).

BP6

Variant 12-56101214-A-T is Benign according to our data. Variant chr12-56101214-A-T is described in ClinVar as [Benign]. Clinvar id is 1178942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-56101214-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.3355A>T	p.Ser1119Cys	missense_variant	Exon 27 of 28	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 link	c.3178A>T	p.Ser1060Cys	missense_variant	Exon 27 of 28		XP_047284456.1
ERBB3	XM_047428501.1 link	c.3178A>T	p.Ser1060Cys	missense_variant	Exon 27 of 28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 link	c.3355A>T	p.Ser1119Cys	missense_variant	Exon 27 of 28	1	NM_001982.4	ENSP00000267101.4		P21860-1
ENSG00000257411	ENST00000548861.2 link	c.-117A>T		upstream_gene_variant		5		ENSP00000449770.3		H0YIN7

Frequencies

GnomAD3 genomes

AF:

0.0952

AC:

14437

AN:

151688

Hom.:

726

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0829

Gnomad AMI

AF:

0.141

Gnomad AMR

AF:

0.0823

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0770

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0788

GnomAD3 exomes

AF:

0.0888

AC:

22324

AN:

251316

Hom.:

1153

AF XY:

0.0904

AC XY:

12280

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0837

Gnomad AMR exome

AF:

0.0515

Gnomad ASJ exome

AF:

0.110

Gnomad EAS exome

AF:

0.00103

Gnomad SAS exome

AF:

0.0770

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.107

AC:

156263

AN:

1461692

Hom.:

9029

Cov.:

AF XY:

0.106

AC XY:

77018

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0848

Gnomad4 AMR exome

AF:

0.0550

Gnomad4 ASJ exome

AF:

0.109

Gnomad4 EAS exome

AF:

0.000579

Gnomad4 SAS exome

AF:

0.0786

Gnomad4 FIN exome

AF:

0.118

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0951

AC:

14444

AN:

151806

Hom.:

727

Cov.:

AF XY:

0.0952

AC XY:

7061

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.0829

Gnomad4 AMR

AF:

0.0822

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0771

Gnomad4 FIN

AF:

0.116

Gnomad4 NFE

AF:

0.110

Gnomad4 OTH

AF:

0.0775

Alfa

AF:

0.104

Hom.:

303

Bravo

AF:

0.0915

TwinsUK

AF:

0.107

AC:

398

ALSPAC

AF:

0.118

AC:

453

ESP6500AA

AF:

0.0872

AC:

384

ESP6500EA

AF:

0.107

AC:

916

ExAC

AF:

0.0908

AC:

11017

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.112

EpiControl

AF:

0.110

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30071039) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.56

T;T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.14

N;.;.;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.64

N;N;.;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.010

D;D;.;D;D

Sift4G

Benign

0.096

T;T;D;D;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.28

MPC

1.0

ClinPred

0.027

GERP RS

5.9

Varity_R

0.079

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over