chr12-56101214-A-T

Variant names:

• chr12-56101214-A-T
• rs773123
• NM_001982.4:c.3355A>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.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 (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.35
• Publications: 56 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000257411 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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.
• 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	c.3355A>T	p.Ser1119Cys	missense_variant	Exon 27 of 28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3178A>T	p.Ser1060Cys	missense_variant	Exon 27 of 28		XP_047284456.1
ERBB3	XM_047428501.1	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	c.3355A>T	p.Ser1119Cys	missense_variant	Exon 27 of 28	1	NM_001982.4	ENSP00000267101.4
ENSG00000257411	ENST00000548861.2	c.-117A>T		upstream_gene_variant		5		ENSP00000449770.3

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

GnomAD2 exomes AF: 0.0888 AC: 22324 AN: 251316 AF XY: 0.0904

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 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

African (AFR) AF: 0.0848 AC: 2837 AN: 33466

American (AMR) AF: 0.0550 AC: 2460 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2844 AN: 26134

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39698

South Asian (SAS) AF: 0.0786 AC: 6784 AN: 86258

European-Finnish (FIN) AF: 0.118 AC: 6286 AN: 53410

Middle Eastern (MID) AF: 0.0867 AC: 500 AN: 5768

European-Non Finnish (NFE) AF: 0.116 AC: 128423 AN: 1111844

Other (OTH) AF: 0.101 AC: 6106 AN: 60396

GnomAD4 genome AF: 0.0951 AC: 14444 AN: 151806 Hom.: 727 Cov.: 30 AF XY: 0.0952 AC XY: 7061 AN XY: 74208

African (AFR) AF: 0.0829 AC: 3430 AN: 41362

American (AMR) AF: 0.0822 AC: 1252 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3464

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5156

South Asian (SAS) AF: 0.0771 AC: 371 AN: 4814

European-Finnish (FIN) AF: 0.116 AC: 1229 AN: 10578

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7471 AN: 67890

Other (OTH) AF: 0.0775 AC: 163 AN: 2104

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

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	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;.;.;.;.
PhyloP100		6.3
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
PromoterAI		-0.056	Neutral
Varity_R		0.079
gMVP		0.26
Mutation Taster		=86/14	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: rs773123; hg19: chr12-56494998; COSMIC: COSV57247854; COSMIC: COSV57247854;