12-56083899-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_001982.4(ERBB3):​c.231G>A​(p.Leu77=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ERBB3
NM_001982.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.220
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
Variant 12-56083899-G-A is Benign according to our data. Variant chr12-56083899-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 749701.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=0.22 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERBB3NM_001982.4 linkuse as main transcriptc.231G>A p.Leu77= synonymous_variant 2/28 ENST00000267101.8 NP_001973.2
ERBB3NM_001005915.1 linkuse as main transcriptc.231G>A p.Leu77= synonymous_variant 2/3 NP_001005915.1
ERBB3XM_047428500.1 linkuse as main transcriptc.54G>A p.Leu18= synonymous_variant 2/28 XP_047284456.1
ERBB3XM_047428501.1 linkuse as main transcriptc.54G>A p.Leu18= synonymous_variant 2/28 XP_047284457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERBB3ENST00000267101.8 linkuse as main transcriptc.231G>A p.Leu77= synonymous_variant 2/281 NM_001982.4 ENSP00000267101 P1P21860-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152100
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000659
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000676
AC:
17
AN:
251492
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000370
Gnomad NFE exome
AF:
0.0000527
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000109
AC:
160
AN:
1461758
Hom.:
0
Cov.:
30
AF XY:
0.000110
AC XY:
80
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000711
Gnomad4 NFE exome
AF:
0.0000989
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000659
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000140
Hom.:
0
Bravo
AF:
0.0000869
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ERBB3-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 01, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
CADD
Benign
8.6
DANN
Benign
0.63
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs199806001; hg19: chr12-56477683; API