12-56080108-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001005915.1(ERBB3):c.-193A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00974 in 557,124 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (9 hom.)
• Consequence: ERBB3 NM_001005915.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.848

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=-0.81).
• BP6: Variant 12-56080108-A-T is Benign according to our data. Variant chr12-56080108-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1316548.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1522/150564) while in subpopulation NFE AF= 0.0136 (922/67556). AF 95% confidence interval is 0.0129. There are 16 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB3	NM_001005915.1	c.-193A>T		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000549061.5	c.-134+174A>T		intron_variant		4
ERBB3	ENST00000549282.5	c.-104-89A>T		intron_variant		4
ERBB3	ENST00000643266.1	c.-96+3225A>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1514 AN: 150456 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00648

Gnomad AMI AF: 0.0265

Gnomad AMR AF: 0.000990

Gnomad ASJ AF: 0.00406

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00336

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00435

GnomAD4 exome AF: 0.00960 AC: 3904 AN: 406560 Hom.: 9 Cov.: 2 AF XY: 0.00936 AC XY: 2021 AN XY: 215936

Gnomad4 AFR exome AF: 0.00737

Gnomad4 AMR exome AF: 0.000706

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.00450

Gnomad4 FIN exome AF: 0.0225

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00847

GnomAD4 genome AF: 0.0101 AC: 1522 AN: 150564 Hom.: 16 Cov.: 33 AF XY: 0.0101 AC XY: 743 AN XY: 73524

Gnomad4 AFR AF: 0.00666

Gnomad4 AMR AF: 0.000989

Gnomad4 ASJ AF: 0.00406

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00336

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.00431

Alfa AF: 0.0200 Hom.: 11

Bravo AF: 0.00716

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.1
Dann	Benign	0.73

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: rs113949839; hg19: chr12-56473892; COSMIC: COSV57260327; COSMIC: COSV57260327;