12-56088138-G-C

Position:

• chr12-56088138-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1 PM2 PP2

The NM_001982.4(ERBB3):​c.850G>C​(p.Gly284Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06

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 Likely_pathogenic. Variant got 7 ACMG points.

• PS1: Transcript NM_001982.4 (ERBB3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376167
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ERBB3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB3	NM_001982.4	c.850G>C	p.Gly284Arg	missense_variant	7/28	ENST00000267101.8
ERBB3	XM_047428500.1	c.673G>C	p.Gly225Arg	missense_variant	7/28
ERBB3	XM_047428501.1	c.673G>C	p.Gly225Arg	missense_variant	7/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8	c.850G>C	p.Gly284Arg	missense_variant	7/28	1	NM_001982.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.96	L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.32	B;.
Vest4		0.53
MutPred		0.73		Loss of ubiquitination at K279 (P = 0.0506);.;
MVP		0.79
MPC		1.2
ClinPred		0.67	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56481922; COSMIC: COSV57249681; COSMIC: COSV57249681;