12-56101239-G-C

Variant names:

• chr12-56101239-G-C
• rs2271188
• NM_001982.4:c.3380G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001982.4(ERBB3):​c.3380G>C​(p.Arg1127Pro) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1127H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51
• 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

ENSG00000257411 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.3380G>C	p.Arg1127Pro	missense_variant	Exon 27 of 28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3203G>C	p.Arg1068Pro	missense_variant	Exon 27 of 28		XP_047284456.1
ERBB3	XM_047428501.1	c.3203G>C	p.Arg1068Pro	missense_variant	Exon 27 of 28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.3380G>C	p.Arg1127Pro	missense_variant	Exon 27 of 28	1	NM_001982.4	ENSP00000267101.4
ENSG00000257411	ENST00000548861.2	c.-92G>C		upstream_gene_variant		5		ENSP00000449770.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	1.6	L;.;.;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N;N;.;D;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;.;D;D
Sift4G	Benign	0.27	T;T;D;D;D
Polyphen		0.93	P;D;.;.;D
Vest4		0.40
MutPred		0.31		Loss of MoRF binding (P = 0.0109);.;.;.;.;
MVP		0.96
MPC		1.2
ClinPred		0.86	D
GERP RS		6.2
PromoterAI		0.064	Neutral
Varity_R		0.32
gMVP		0.41
Mutation Taster		=45/55	disease causing

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: rs2271188; hg19: chr12-56495023;