12-56083757-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_001982.4(ERBB3):c.89C>T(p.Pro30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,048 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.90

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ERBB3
• BP4: Computational evidence support a benign effect (MetaRNN=0.01344651).
• BP6: Variant 12-56083757-C-T is Benign according to our data. Variant chr12-56083757-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 806898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00236 (359/152196) while in subpopulation SAS AF= 0.00332 (16/4826). AF 95% confidence interval is 0.0025. There are 1 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB3	NM_001982.4	c.89C>T	p.Pro30Leu	missense_variant	2/28	ENST00000267101.8
ERBB3	NM_001005915.1	c.89C>T	p.Pro30Leu	missense_variant	2/3
ERBB3	XM_047428500.1	c.-89C>T		5_prime_UTR_variant	2/28
ERBB3	XM_047428501.1	c.-89C>T		5_prime_UTR_variant	2/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB3	ENST00000267101.8	c.89C>T	p.Pro30Leu	missense_variant	2/28	1	NM_001982.4	P1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00227 AC: 572 AN: 251490 Hom.: 1 AF XY: 0.00229 AC XY: 311 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00859

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00172 AC: 2514 AN: 1461852 Hom.: 7 Cov.: 31 AF XY: 0.00179 AC XY: 1305 AN XY: 727222

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00293

Gnomad4 FIN exome AF: 0.00770

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74418

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00225 Hom.: 2

Bravo AF: 0.00170

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ERBB3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

ERBB3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Benign	0.81
DEOGEN2	Benign	0.36	T;D;.
Eigen	Benign	-0.0050
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.090	T;T;T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.0070, 0.91	.;B;P
Vest4		0.56, 0.54
MVP		0.92
MPC		0.35
ClinPred		0.041	T
GERP RS		5.4
Varity_R		0.38
gMVP		0.55

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: rs56017157; hg19: chr12-56477541;