12-56102035-G-T

Variant names:

• chr12-56102035-G-T
• rs755855285
• NM_001982.4:c.4009G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001982.4(ERBB3):​c.4009G>T​(p.Ala1337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A1337T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-56102035-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253223.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13724667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.4009G>T	p.Ala1337Ser	missense_variant	Exon 28 of 28	ENST00000267101.8	NP_001973.2
ERBB3	XM_047428500.1	c.3832G>T	p.Ala1278Ser	missense_variant	Exon 28 of 28		XP_047284456.1
ERBB3	XM_047428501.1	c.3832G>T	p.Ala1278Ser	missense_variant	Exon 28 of 28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.4009G>T	p.Ala1337Ser	missense_variant	Exon 28 of 28	1	NM_001982.4	ENSP00000267101.4
ENSG00000257411	ENST00000548861.2	c.31+674G>T		intron_variant	Intron 1 of 5	5		ENSP00000449770.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458680 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725848

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T;.;T;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PhyloP100		2.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.080	N;N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;T;.;T;D
Sift4G	Benign	0.71	T;T;T;T;T
Polyphen		0.012	B;B;.;.;B
Vest4		0.094
MutPred		0.17		Gain of glycosylation at A1337 (P = 0.0232);.;.;.;.;
MVP		0.79
MPC		0.30
ClinPred		0.38	T
GERP RS		4.4
Varity_R		0.071
gMVP		0.26
Mutation Taster		=80/20	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: rs755855285; hg19: chr12-56495819;