12-56083889-T-G

Position:

• chr12-56083889-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001982.4(ERBB3):​c.221T>G​(p.Leu74Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.57

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.

• 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). GenCC has associacion of gene with Hirschsprung disease, lethal congenital contracture syndrome 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB3	NM_001982.4	c.221T>G	p.Leu74Arg	missense_variant	2/28	ENST00000267101.8	NP_001973.2
ERBB3	NM_001005915.1	c.221T>G	p.Leu74Arg	missense_variant	2/3		NP_001005915.1
ERBB3	XM_047428500.1	c.44T>G	p.Leu15Arg	missense_variant	2/28		XP_047284456.1
ERBB3	XM_047428501.1	c.44T>G	p.Leu15Arg	missense_variant	2/28		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8	c.221T>G	p.Leu74Arg	missense_variant	2/28	1	NM_001982.4	ENSP00000267101	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;D;.;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.1	.;D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;D;.;.
Vest4		0.86, 0.92, 0.91
MutPred		0.83		.;Gain of MoRF binding (P = 0.0528);.;Gain of MoRF binding (P = 0.0528);Gain of MoRF binding (P = 0.0528);.;.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.92
gMVP		0.92

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: rs1565855722; hg19: chr12-56477673;