rs2271188

Variant names:

• chr12-56101239-G-A
• rs2271188
• NM_001982.4:c.3380G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-56101239-G-A
• chr12-56101239-G-C
• chr12-56101239-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001982.4(ERBB3):​c.3380G>A​(p.Arg1127His) variant causes a missense change. The variant allele was found at a frequency of 0.000502 in 1,614,040 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00071 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00048 (7 hom.)
• Consequence: ERBB3 NM_001982.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.51
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008962393).
• BP6: Variant 12-56101239-G-A is Benign according to our data. Variant chr12-56101239-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 713497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00071 (108/152156) while in subpopulation EAS AF = 0.0116 (60/5168). AF 95% confidence interval is 0.00926. There are 4 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	NM_001982.4	MANE Select	c.3380G>A	p.Arg1127His	missense	Exon 27 of 28	NP_001973.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB3	ENST00000267101.8	TSL:1 MANE Select	c.3380G>A	p.Arg1127His	missense	Exon 27 of 28	ENSP00000267101.4
	ERBB3	ENST00000550070.6	TSL:1	c.1301G>A	p.Arg434His	missense	Exon 12 of 13	ENSP00000448946.2
	ERBB3	ENST00000551242.5	TSL:1	n.*235G>A		non_coding_transcript_exon	Exon 10 of 11	ENSP00000447510.1

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 152038 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000744 AC: 187 AN: 251366 AF XY: 0.000699

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00745

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000480 AC: 702 AN: 1461884 Hom.: 7 Cov.: 33 AF XY: 0.000518 AC XY: 377 AN XY: 727242

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.0120 AC: 476 AN: 39700

South Asian (SAS) AF: 0.000985 AC: 85 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1112004

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.000710 AC: 108 AN: 152156 Hom.: 4 Cov.: 30 AF XY: 0.000672 AC XY: 50 AN XY: 74402

African (AFR) AF: 0.0000241 AC: 1 AN: 41498

American (AMR) AF: 0.00177 AC: 27 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5168

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00106 Hom.: 35

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ERBB3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.029	D
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.17
MVP		0.95
MPC		1.1
ClinPred		0.091	T
GERP RS		6.2
PromoterAI		0.053	Neutral
Varity_R		0.041
gMVP		0.30
Mutation Taster		=75/25	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: rs2271188; hg19: chr12-56495023; COSMIC: COSV57252825; COSMIC: COSV57252825;