rs2271188

Positions:

chr12-56101239-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERBB3. . Gene score misZ 1.3904 (greater than the threshold 3.09). Trascript score misZ 3.2897 (greater than threshold 3.09). GenCC has associacion of gene with Hirschsprung disease, lethal congenital contracture syndrome 2.

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 GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ERBB3	NM_001982.4 linkuse as main transcript	c.3380G>A	p.Arg1127His	missense_variant	27/28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1 linkuse as main transcript	c.3203G>A	p.Arg1068His	missense_variant	27/28		XP_047284456.1
ERBB3	XM_047428501.1 linkuse as main transcript	c.3203G>A	p.Arg1068His	missense_variant	27/28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 linkuse as main transcript	c.3380G>A	p.Arg1127His	missense_variant	27/28	1	NM_001982.4	ENSP00000267101	P1	P21860-1

Frequencies

GnomAD3 genomes

AF:

0.000671

AC:

102

AN:

152038

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000699

AC XY:

AN XY:

135880

show subpopulations

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.:

Cov.:

AF XY:

0.000518

AC XY:

377

AN XY:

727242

show subpopulations

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.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74402

show subpopulations

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.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000774

AC:

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	This variant is associated with the following publications: (PMID: 23856252) -

ERBB3-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

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

LIST_S2

Benign

0.73

T;T;T;T;T

MetaRNN

Benign

0.0090

T;T;T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.6

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.54

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

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

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