rs773123

chr12-56101214-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.095 (727 hom., cov: 30)
  • Exomes 𝑓: 0.11 (9029 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.35

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ERBB3
• 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_single_submitter, 1 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/exons	MANE	UniProt
ERBB3	NM_001982.4	c.3355A>T	p.Ser1119Cys	missense_variant	27/28	ENST00000267101.8
ERBB3	XM_047428500.1	c.3178A>T	p.Ser1060Cys	missense_variant	27/28
ERBB3	XM_047428501.1	c.3178A>T	p.Ser1060Cys	missense_variant	27/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8	c.3355A>T	p.Ser1119Cys	missense_variant	27/28	1	NM_001982.4	P1

Frequencies

GnomAD3 genomes AF: 0.0952 AC: 14437 AN: 151688 Hom.: 726 Cov.: 30

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

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.: 34 AF XY: 0.106 AC XY: 77018 AN XY: 727148

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.: 30 AF XY: 0.0952 AC XY: 7061 AN XY: 74208

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2019

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	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	25
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	D
LIST_S2	Benign	0.56	T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.14	N;.;.;.;.
MutationTaster	Benign	0.000090	P;P;P;P;P;P
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs773123; hg19: chr12-56494998; COSMIC: COSV57247854; COSMIC: COSV57247854;