Variant 12-56093417-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001982.4(ERBB3):c.1347T>C(p.Ile449Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 1,613,794 control chromosomes in the GnomAD database, including 4,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 423 hom., cov: 31)

Exomes 𝑓: 0.074 ( 4323 hom. )

Consequence

ERBB3
NM_001982.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.61

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:

ERBB3 (HGNC:):

ERBB3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-56093417-T-C is Benign according to our data. Variant chr12-56093417-T-C is described in ClinVar as [Benign]. Clinvar id is 1269955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4 linkuse as main transcript	c.1347T>C	p.Ile449Ile	synonymous_variant	12/28	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 linkuse as main transcript	c.1170T>C	p.Ile390Ile	synonymous_variant	12/28		XP_047284456.1
ERBB3	XM_047428501.1 linkuse as main transcript	c.1170T>C	p.Ile390Ile	synonymous_variant	12/28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 linkuse as main transcript	c.1347T>C	p.Ile449Ile	synonymous_variant	12/28	1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11093

AN:

151984

Hom.:

422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0767

Gnomad AMI

AF:

0.0890

Gnomad AMR

AF:

0.0614

Gnomad ASJ

AF:

0.0741

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0540

Gnomad FIN

AF:

0.0998

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0761

Gnomad OTH

AF:

0.0578

GnomAD3 exomes

AF:

0.0646

AC:

16254

AN:

251420

Hom.:

604

AF XY:

0.0656

AC XY:

8907

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0786

Gnomad AMR exome

AF:

0.0370

Gnomad ASJ exome

AF:

0.0724

Gnomad EAS exome

AF:

0.000870

Gnomad SAS exome

AF:

0.0522

Gnomad FIN exome

AF:

0.0996

Gnomad NFE exome

AF:

0.0768

Gnomad OTH exome

AF:

0.0759

GnomAD4 exome

AF:

0.0742

AC:

108389

AN:

1461692

Hom.:

4323

Cov.:

AF XY:

0.0736

AC XY:

53513

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0798

Gnomad4 AMR exome

AF:

0.0394

Gnomad4 ASJ exome

AF:

0.0716

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.0535

Gnomad4 FIN exome

AF:

0.0986

Gnomad4 NFE exome

AF:

0.0788

Gnomad4 OTH exome

AF:

0.0705

GnomAD4 genome

AF:

0.0730

AC:

11102

AN:

152102

Hom.:

423

Cov.:

AF XY:

0.0740

AC XY:

5503

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0767

Gnomad4 AMR

AF:

0.0613

Gnomad4 ASJ

AF:

0.0741

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.0541

Gnomad4 FIN

AF:

0.0998

Gnomad4 NFE

AF:

0.0761

Gnomad4 OTH

AF:

0.0567

Alfa

AF:

0.0728

Hom.:

258

Bravo

AF:

0.0693

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0778

EpiControl

AF:

0.0782

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.7

DANN

Benign

0.69

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.

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