12-56083910-A-T

Position:

chr12-56083910-A-T

Variant summary

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

The NM_001982.4(ERBB3):c.234+8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,612,718 control chromosomes in the GnomAD database, including 283,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 23400 hom., cov: 31)

Exomes 𝑓: 0.59 ( 260096 hom. )

Consequence

ERBB3
NM_001982.4 splice_region, intron

Scores

Splicing: ADA: 0.00002307

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.44

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=-0.9).

BP6

Variant 12-56083910-A-T is Benign according to our data. Variant chr12-56083910-A-T is described in ClinVar as [Benign]. Clinvar id is 1255390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ERBB3	NM_001982.4 linkuse as main transcript	c.234+8A>T	splice_region_variant, intron_variant	ENST00000267101.8
ERBB3	NM_001005915.1 linkuse as main transcript	c.234+8A>T	splice_region_variant, intron_variant
ERBB3	XM_047428500.1 linkuse as main transcript	c.57+8A>T	splice_region_variant, intron_variant
ERBB3	XM_047428501.1 linkuse as main transcript	c.57+8A>T	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8 linkuse as main transcript	c.234+8A>T		splice_region_variant, intron_variant		1	NM_001982.4	P1	P21860-1

Frequencies

GnomAD3 genomes

AF:

0.537

AC:

81553

AN:

151770

Hom.:

23374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.332

Gnomad AMI

AF:

0.419

Gnomad AMR

AF:

0.662

Gnomad ASJ

AF:

0.542

Gnomad EAS

AF:

0.779

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.619

Gnomad MID

AF:

0.685

Gnomad NFE

AF:

0.589

Gnomad OTH

AF:

0.583

GnomAD3 exomes

AF:

0.627

AC:

157568

AN:

251466

Hom.:

51093

AF XY:

0.631

AC XY:

85732

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.322

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.559

Gnomad EAS exome

AF:

0.784

Gnomad SAS exome

AF:

0.716

Gnomad FIN exome

AF:

0.611

Gnomad NFE exome

AF:

0.587

Gnomad OTH exome

AF:

0.626

GnomAD4 exome

AF:

0.592

AC:

864467

AN:

1460832

Hom.:

260096

Cov.:

AF XY:

0.596

AC XY:

433344

AN XY:

726744

show subpopulations

Gnomad4 AFR exome

AF:

0.321

Gnomad4 AMR exome

AF:

0.755

Gnomad4 ASJ exome

AF:

0.553

Gnomad4 EAS exome

AF:

0.793

Gnomad4 SAS exome

AF:

0.714

Gnomad4 FIN exome

AF:

0.600

Gnomad4 NFE exome

AF:

0.576

Gnomad4 OTH exome

AF:

0.595

GnomAD4 genome

AF:

0.537

AC:

81617

AN:

151886

Hom.:

23400

Cov.:

AF XY:

0.547

AC XY:

40595

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.333

Gnomad4 AMR

AF:

0.662

Gnomad4 ASJ

AF:

0.542

Gnomad4 EAS

AF:

0.779

Gnomad4 SAS

AF:

0.720

Gnomad4 FIN

AF:

0.619

Gnomad4 NFE

AF:

0.589

Gnomad4 OTH

AF:

0.587

Alfa

AF:

0.571

Hom.:

8111

Bravo

AF:

0.528

Asia WGS

AF:

0.771

AC:

2680

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lethal congenital contracture syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Visceral neuropathy, familial

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.065

DANN

Benign

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

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