rs188955993

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000411731.6(ERBB3):c.544G>A(p.Ala182Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00074 in 1,580,006 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A182S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00074 ( 15 hom. )

Consequence

ERBB3
ENST00000411731.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.477

Publications

4 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030994415).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000723 (110/152152) while in subpopulation AMR AF = 0.00491 (75/15270). AF 95% confidence interval is 0.00402. There are 2 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.421+123G>A		intron_variant	Intron 3 of 27	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	NM_001005915.1 link	c.544G>A	p.Ala182Thr	missense_variant	Exon 3 of 3		NP_001005915.1	P21860-2
ERBB3	XM_047428500.1 link	c.244+123G>A		intron_variant	Intron 3 of 27		XP_047284456.1
ERBB3	XM_047428501.1 link	c.244+123G>A		intron_variant	Intron 3 of 27		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 link	c.421+123G>A		intron_variant	Intron 3 of 27	1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.000730

AC:

111

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00492

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00368

AC:

782

AN:

212762

AF XY:

0.00284

show subpopulations

Gnomad AFR exome

AF:

0.000360

Gnomad AMR exome

AF:

0.0222

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00494

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00209

GnomAD4 exome

AF:

0.000742

AC:

1059

AN:

1427854

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

474

AN XY:

705666

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32778

American (AMR)

AF:

0.0192

AC:

785

AN:

40886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24312

East Asian (EAS)

AF:

0.00498

AC:

195

AN:

39152

South Asian (SAS)

AF:

0.000389

AC:

AN:

82298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52296

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.0000266

AC:

AN:

1091630

Other (OTH)

AF:

0.000255

AC:

AN:

58874

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000723

AC:

110

AN:

152152

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41500

American (AMR)

AF:

0.00491

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00406

AC:

AN:

5170

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000389

Hom.:

Bravo

AF:

0.00158

ExAC

AF:

0.00269

AC:

324

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.95

(source)

DANN

Benign

0.40

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

PhyloP100

-0.48

PROVEAN

Benign

0.27

REVEL

Benign

0.0030

Sift

Pathogenic

0.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.085

MVP

0.15

ClinPred

0.0030

GERP RS

-1.3

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over