chr12-56085304-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005915.1(ERBB3):​c.544G>T​(p.Ala182Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,427,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ERBB3
NM_001005915.1 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.477
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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061238647).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERBB3NM_001982.4 linkc.421+123G>T intron_variant Intron 3 of 27 ENST00000267101.8 NP_001973.2 P21860-1
ERBB3NM_001005915.1 linkc.544G>T p.Ala182Ser missense_variant Exon 3 of 3 NP_001005915.1 P21860-2
ERBB3XM_047428500.1 linkc.244+123G>T intron_variant Intron 3 of 27 XP_047284456.1
ERBB3XM_047428501.1 linkc.244+123G>T intron_variant Intron 3 of 27 XP_047284457.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERBB3ENST00000267101.8 linkc.421+123G>T intron_variant Intron 3 of 27 1 NM_001982.4 ENSP00000267101.4 P21860-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000280
AC:
4
AN:
1427856
Hom.:
0
Cov.:
32
AF XY:
0.00000283
AC XY:
2
AN XY:
705666
show subpopulations
African (AFR)
AF:
0.0000305
AC:
1
AN:
32778
American (AMR)
AF:
0.00
AC:
0
AN:
40888
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24312
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39152
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82298
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52296
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5628
European-Non Finnish (NFE)
AF:
0.00000275
AC:
3
AN:
1091630
Other (OTH)
AF:
0.00
AC:
0
AN:
58874
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
0.30
DANN
Benign
0.83
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.21
T
M_CAP
Benign
0.0019
T
MetaRNN
Benign
0.061
T
MetaSVM
Benign
-1.0
T
PhyloP100
-0.48
PROVEAN
Benign
0.29
N
REVEL
Benign
0.0020
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.31
T
Polyphen
0.0
B
Vest4
0.11
MVP
0.24
ClinPred
0.035
T
GERP RS
-1.3
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs188955993; hg19: chr12-56479088; API