dbSNP rs7297175: ERBB3:c.-96+90T>C (chr12-56080024-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000549282.5(ERBB3):c.-105+90T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 530,504 control chromosomes in the GnomAD database, including 98,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26297 hom., cov: 32)

Exomes 𝑓: 0.61 ( 72473 hom. )

Consequence

ERBB3
ENST00000549282.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.84

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-56080024-T-C is Benign according to our data. Variant chr12-56080024-T-C is described in ClinVar as [Benign]. Clinvar id is 1292949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.-277T>C		upstream_gene_variant		ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	NM_001005915.1 link	c.-277T>C		upstream_gene_variant			NP_001005915.1	P21860-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 link	c.-277T>C		upstream_gene_variant		1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.584

AC:

88698

AN:

151886

Hom.:

26266

Cov.:

show subpopulations

Gnomad AFR

AF:

0.507

Gnomad AMI

AF:

0.419

Gnomad AMR

AF:

0.677

Gnomad ASJ

AF:

0.550

Gnomad EAS

AF:

0.772

Gnomad SAS

AF:

0.719

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.587

Gnomad OTH

AF:

0.602

GnomAD4 exome

AF:

0.613

AC:

231913

AN:

378498

Hom.:

72473

Cov.:

AF XY:

0.619

AC XY:

122527

AN XY:

197970

show subpopulations

Gnomad4 AFR exome

AF:

0.504

Gnomad4 AMR exome

AF:

0.717

Gnomad4 ASJ exome

AF:

0.551

Gnomad4 EAS exome

AF:

0.789

Gnomad4 SAS exome

AF:

0.707

Gnomad4 FIN exome

AF:

0.568

Gnomad4 NFE exome

AF:

0.583

Gnomad4 OTH exome

AF:

0.599

GnomAD4 genome

AF:

0.584

AC:

88766

AN:

152006

Hom.:

26297

Cov.:

AF XY:

0.590

AC XY:

43848

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.508

Gnomad4 AMR

AF:

0.677

Gnomad4 ASJ

AF:

0.550

Gnomad4 EAS

AF:

0.772

Gnomad4 SAS

AF:

0.718

Gnomad4 FIN

AF:

0.592

Gnomad4 NFE

AF:

0.588

Gnomad4 OTH

AF:

0.603

Alfa

AF:

0.577

Hom.:

3593

Bravo

AF:

0.585

Asia WGS

AF:

0.743

AC:

2583

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23060569) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.4

DANN

Benign

0.61

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