chr12-56083757-C-T

Variant names:

• chr12-56083757-C-T
• rs56017157
• NM_001982.4:c.89C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.90
• Publications: 14 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• visceral neuropathy, familial, 1, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 806898.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00172 (2514/1461852) while in subpopulation MID AF = 0.00572 (33/5768). AF 95% confidence interval is 0.00419. There are 7 homozygotes in GnomAdExome4. There are 1305 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 2 of 28	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.89C>T	p.Pro30Leu	missense	Exon 2 of 3	NP_001005915.1	P21860-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.89C>T	p.Pro30Leu	missense	Exon 2 of 28	ENSP00000267101.4	P21860-1
	ERBB3	ENST00000411731.6	TSL:1	c.89C>T	p.Pro30Leu	missense	Exon 2 of 3	ENSP00000415753.2	P21860-2
	ERBB3	ENST00000551242.5	TSL:1	n.89C>T		non_coding_transcript_exon	Exon 2 of 11	ENSP00000447510.1	P21860-3

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

GnomAD2 exomes AF: 0.00227 AC: 572 AN: 251490 AF XY: 0.00229

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 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

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000939 AC: 42 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00293 AC: 253 AN: 86254

European-Finnish (FIN) AF: 0.00770 AC: 411 AN: 53410

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.00148 AC: 1642 AN: 1111988

Other (OTH) AF: 0.00192 AC: 116 AN: 60396

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

African (AFR) AF: 0.000289 AC: 12 AN: 41536

American (AMR) AF: 0.00262 AC: 40 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00216 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	ERBB3-related disorder (1)
-	1	-	Lethal congenital contracture syndrome 2;C1855733:Visceral neuropathy, familial, 1, autosomal recessive;C5552985:Erythroleukemia, familial, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.0050
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.10
Sift	Benign	0.090	T
Sift4G	Benign	0.67	T
Polyphen		0.0070	B
Vest4		0.56
MVP		0.92
MPC		0.35
ClinPred		0.041	T
GERP RS		5.4
PromoterAI		0.017	Neutral
Varity_R		0.38
gMVP		0.55
Mutation Taster		=91/9	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: rs56017157; hg19: chr12-56477541;