12-56085070-G-C

Variant names:

• chr12-56085070-G-C
• rs1057519893
• NM_001982.4:c.310G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001982.4(ERBB3):​c.310G>C​(p.Val104Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V104M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.31
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-56085070-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376410.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.310G>C	p.Val104Leu	missense	Exon 3 of 28	NP_001973.2
	ERBB3	NM_001005915.1		c.310G>C	p.Val104Leu	missense	Exon 3 of 3	NP_001005915.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.310G>C	p.Val104Leu	missense	Exon 3 of 28	ENSP00000267101.4
	ERBB3	ENST00000411731.6	TSL:1	c.310G>C	p.Val104Leu	missense	Exon 3 of 3	ENSP00000415753.2
	ERBB3	ENST00000551242.5	TSL:1	n.310G>C		non_coding_transcript_exon	Exon 3 of 11	ENSP00000447510.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.044
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.47
Sift	Benign	0.13	T
Sift4G	Benign	0.27	T
Polyphen		0.28	B
Vest4		0.52
MutPred		0.68		Gain of sheet (P = 0.1208)
MVP		0.83
MPC		0.45
ClinPred		0.60	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.35
gMVP		0.72
Mutation Taster		=71/29	polymorphism

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: rs1057519893; hg19: chr12-56478854; COSMIC: COSV57253558; COSMIC: COSV57253558;