chr12-56080024-T-C

Variant names:

• chr12-56080024-T-C
• rs7297175
• ENST00000926495.1:c.-102+90T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.84
• Publications: 35 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: Benign. The variant received -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 VariationId 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.

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.-277T>C		upstream_gene	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.-277T>C		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+90T>C		intron	N/A	ENSP00000596554.1
	ERBB3	ENST00000683059.1		c.-96+90T>C		intron	N/A	ENSP00000507402.1	P21860-4
	ERBB3	ENST00000549282.5	TSL:4	c.-105+90T>C		intron	N/A	ENSP00000448636.1	F8VRL0

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88698 AN: 151886 Hom.: 26266 Cov.: 32

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.: 0 AF XY: 0.619 AC XY: 122527 AN XY: 197970

African (AFR) AF: 0.504 AC: 5126 AN: 10166

American (AMR) AF: 0.717 AC: 11075 AN: 15452

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 6584 AN: 11958

East Asian (EAS) AF: 0.789 AC: 19690 AN: 24958

South Asian (SAS) AF: 0.707 AC: 28980 AN: 40990

European-Finnish (FIN) AF: 0.568 AC: 13653 AN: 24044

Middle Eastern (MID) AF: 0.685 AC: 1141 AN: 1666

European-Non Finnish (NFE) AF: 0.583 AC: 132252 AN: 226884

Other (OTH) AF: 0.599 AC: 13412 AN: 22380

GnomAD4 genome AF: 0.584 AC: 88766 AN: 152006 Hom.: 26297 Cov.: 32 AF XY: 0.590 AC XY: 43848 AN XY: 74286

African (AFR) AF: 0.508 AC: 21051 AN: 41470

American (AMR) AF: 0.677 AC: 10353 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1908 AN: 3466

East Asian (EAS) AF: 0.772 AC: 3972 AN: 5142

South Asian (SAS) AF: 0.718 AC: 3463 AN: 4822

European-Finnish (FIN) AF: 0.592 AC: 6257 AN: 10568

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39909 AN: 67930

Other (OTH) AF: 0.603 AC: 1273 AN: 2112

Alfa AF: 0.575 Hom.: 3698

Bravo AF: 0.585

Asia WGS AF: 0.743 AC: 2583 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.4
DANN	Benign	0.61
PhyloP100		-1.8
PromoterAI		-0.099	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs7297175; hg19: chr12-56473808;