12-56079996-G-T

Variant names:

• chr12-56079996-G-T
• rs115699610
• ENST00000926495.1:c.-102+62G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000549282.5(ERBB3):​c.-105+62G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000293 in 341,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ERBB3 ENST00000549282.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.471
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000549282.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.-305G>T		upstream_gene	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.-305G>T		upstream_gene	N/A	NP_001005915.1	P21860-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000926495.1		c.-102+62G>T		intron	N/A	ENSP00000596554.1
	ERBB3	ENST00000683059.1		c.-96+62G>T		intron	N/A	ENSP00000507402.1	P21860-4
	ERBB3	ENST00000549282.5	TSL:4	c.-105+62G>T		intron	N/A	ENSP00000448636.1	F8VRL0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000293 AC: 1 AN: 341204 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 177394

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9240

American (AMR) AF: 0.00 AC: 0 AN: 13744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11168

East Asian (EAS) AF: 0.00 AC: 0 AN: 22352

South Asian (SAS) AF: 0.00 AC: 0 AN: 37614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1500

European-Non Finnish (NFE) AF: 0.00000490 AC: 1 AN: 204098

Other (OTH) AF: 0.00 AC: 0 AN: 20494

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.47
PromoterAI		-0.12	Neutral

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

Other links and lift over

dbSNP: rs115699610; hg19: chr12-56473780;