rs2292238

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001982.4(ERBB3):c.3129+9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,612,632 control chromosomes in the GnomAD database, including 122,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9193 hom., cov: 32)

Exomes 𝑓: 0.39 ( 113517 hom. )

Consequence

ERBB3
NM_001982.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.18

Publications

28 publications found

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 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

ERBB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 12-56100038-A-C is Benign according to our data. Variant chr12-56100038-A-C is described in ClinVar as Benign. ClinVar VariationId is 1226099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.3129+9A>C	intron_variant	Intron 25 of 27	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 link	c.2952+9A>C	intron_variant	Intron 25 of 27		XP_047284456.1
ERBB3	XM_047428501.1 link	c.2952+9A>C	intron_variant	Intron 25 of 27		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 link	c.3129+9A>C		intron_variant	Intron 25 of 27	1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.334

AC:

50818

AN:

151994

Hom.:

9179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.505

Gnomad AMR

AF:

0.360

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.341

Gnomad SAS

AF:

0.293

Gnomad FIN

AF:

0.379

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.407

Gnomad OTH

AF:

0.346

GnomAD2 exomes

AF:

0.365

AC:

91819

AN:

251364

AF XY:

0.365

show subpopulations

Gnomad AFR exome

AF:

0.185

Gnomad AMR exome

AF:

0.376

Gnomad ASJ exome

AF:

0.399

Gnomad EAS exome

AF:

0.337

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.405

Gnomad OTH exome

AF:

0.371

GnomAD4 exome

AF:

0.391

AC:

570683

AN:

1460520

Hom.:

113517

Cov.:

AF XY:

0.389

AC XY:

282694

AN XY:

726604

show subpopulations

African (AFR)

AF:

0.179

AC:

6002

AN:

33450

American (AMR)

AF:

0.377

AC:

16842

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.406

AC:

10616

AN:

26128

East Asian (EAS)

AF:

0.342

AC:

13563

AN:

39694

South Asian (SAS)

AF:

0.294

AC:

25357

AN:

86104

European-Finnish (FIN)

AF:

0.392

AC:

20922

AN:

53410

Middle Eastern (MID)

AF:

0.290

AC:

1672

AN:

5762

European-Non Finnish (NFE)

AF:

0.408

AC:

452851

AN:

1110910

Other (OTH)

AF:

0.379

AC:

22858

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

19561

39123

58684

78246

97807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13910

27820

41730

55640

69550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.334

AC:

50874

AN:

152112

Hom.:

9193

Cov.:

AF XY:

0.332

AC XY:

24718

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.186

AC:

7728

AN:

41490

American (AMR)

AF:

0.359

AC:

5498

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1501

AN:

3472

East Asian (EAS)

AF:

0.342

AC:

1766

AN:

5168

South Asian (SAS)

AF:

0.294

AC:

1418

AN:

4820

European-Finnish (FIN)

AF:

0.379

AC:

4016

AN:

10590

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.407

AC:

27657

AN:

67956

Other (OTH)

AF:

0.345

AC:

731

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1702

3404

5106

6808

8510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.373

Hom.:

6272

Bravo

AF:

0.329

Asia WGS

AF:

0.342

AC:

1189

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Lethal congenital contracture syndrome 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Visceral neuropathy, familial

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.3

(source)

DANN

Benign

0.70

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over