12-56093378-G-C

Position:

• chr12-56093378-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001982.4(ERBB3):​c.1308G>C​(p.Leu436Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERBB3. . Gene score misZ: 1.3904 (greater than the threshold 3.09). Trascript score misZ: 3.2897 (greater than threshold 3.09). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. GenCC has associacion of the gene with Hirschsprung disease, lethal congenital contracture syndrome 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29954284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.1308G>C	p.Leu436Phe	missense_variant	12/28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.1131G>C	p.Leu377Phe	missense_variant	12/28		XP_047284456.1
ERBB3	XM_047428501.1	c.1131G>C	p.Leu377Phe	missense_variant	12/28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.1308G>C	p.Leu436Phe	missense_variant	12/28	1	NM_001982.4	ENSP00000267101.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.91	L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.096	T;T
Sift4G	Benign	0.062	T;T
Polyphen		0.045	B;.
Vest4		0.34
MutPred		0.58		Gain of MoRF binding (P = 0.1201);.;
MVP		0.85
MPC		0.50
ClinPred		0.21	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229045; hg19: chr12-56487162;