Genetic Variant NM_001982.4:c.3348G>T (chr12-56101207-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001982.4(ERBB3):c.3348G>T(p.Arg1116Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R1116R) has been classified as Benign.

Frequency

Genomes: not found (cov: 30)

Consequence

ERBB3
NM_001982.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.554

Variant links:

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 links:

ENSG00000257411 (HGNC:):

ENSG00000257411 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ERBB3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.3904 (below the threshold of 3.09). Trascript score misZ: 3.2897 (above the threshold of 3.09). GenCC associations: The gene is linked to Hirschsprung disease, lethal congenital contracture syndrome 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.15474477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.3348G>T	p.Arg1116Ser	missense_variant	Exon 27 of 28	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 link	c.3171G>T	p.Arg1057Ser	missense_variant	Exon 27 of 28		XP_047284456.1
ERBB3	XM_047428501.1 link	c.3171G>T	p.Arg1057Ser	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 link	c.3348G>T	p.Arg1116Ser	missense_variant	Exon 27 of 28	1	NM_001982.4	ENSP00000267101.4		P21860-1
ENSG00000257411	ENST00000548861.2 link	c.-124G>T		upstream_gene_variant		5		ENSP00000449770.3		H0YIN7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.31

CADD

Benign

9.2

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;.;T;T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

N;.;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

0.64

N;N;.;N;N

REVEL

Benign

0.20

Sift

Benign

0.12

T;T;.;T;T

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

0.030

B;B;.;.;B

Vest4

0.25

MutPred

0.33

Gain of phosphorylation at R1116 (P = 0.0096);.;.;.;.;

MVP

0.78

MPC

0.37

ClinPred

0.17

GERP RS

-0.82

Varity_R

0.12

gMVP

0.18

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over