12-56084823-G-A

Position:

• chr12-56084823-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001982.4(ERBB3):​c.235-172G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0743 in 151,908 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.074 (458 hom., cov: 30)
• Consequence: ERBB3 NM_001982.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.380

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-56084823-G-A is Benign according to our data. Variant chr12-56084823-G-A is described in ClinVar as [Benign]. Clinvar id is 1295721.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.235-172G>A		intron_variant		ENST00000267101.8	NP_001973.2
ERBB3	NM_001005915.1	c.235-172G>A		intron_variant			NP_001005915.1
ERBB3	XM_047428500.1	c.58-172G>A		intron_variant			XP_047284456.1
ERBB3	XM_047428501.1	c.58-172G>A		intron_variant			XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.235-172G>A		intron_variant		1	NM_001982.4	ENSP00000267101	P1

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11275 AN: 151790 Hom.: 456 Cov.: 30

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.0610

Gnomad ASJ AF: 0.0742

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0765

Gnomad OTH AF: 0.0624

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0743 AC: 11289 AN: 151908 Hom.: 458 Cov.: 30 AF XY: 0.0753 AC XY: 5587 AN XY: 74244

Gnomad4 AFR AF: 0.0811

Gnomad4 AMR AF: 0.0610

Gnomad4 ASJ AF: 0.0742

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0529

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0765

Gnomad4 OTH AF: 0.0613

Alfa AF: 0.0751 Hom.: 62

Bravo AF: 0.0705

Asia WGS AF: 0.0290 AC: 101 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.93
CADD	Benign	1.0
DANN	Benign	0.60

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

Other links and lift over

dbSNP: rs12817471; hg19: chr12-56478607;