rs74094518

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The ENST00000549282.5(ERBB3):c.-104-91T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 511,096 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 94 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 21 hom. )

Consequence

ERBB3
ENST00000549282.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.70

Publications

3 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
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=-0.83).

BP6

Variant 12-56080106-T-A is Benign according to our data. Variant chr12-56080106-T-A is described in ClinVar as Benign. ClinVar VariationId is 1283687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000549282.5. 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.-195T>A		upstream_gene	N/A	NP_001973.2	P21860-1
	ERBB3	NM_001005915.1		c.-195T>A		upstream_gene	N/A	NP_001005915.1	P21860-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERBB3	ENST00000926495.1		c.-101-94T>A	intron	N/A	ENSP00000596554.1
ERBB3	ENST00000683059.1		c.-96+172T>A	intron	N/A	ENSP00000507402.1	P21860-4
ERBB3	ENST00000549282.5	TSL:4	c.-104-91T>A	intron	N/A	ENSP00000448636.1	F8VRL0

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2799

AN:

150738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0645

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00529

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000835

Gnomad FIN

AF:

0.0000970

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000414

Gnomad OTH

AF:

0.0160

GnomAD4 exome

AF:

0.00412

AC:

1483

AN:

360240

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

748

AN XY:

191086

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0747

AC:

768

AN:

10280

American (AMR)

AF:

0.00602

AC:

109

AN:

18116

Ashkenazi Jewish (ASJ)

AF:

0.000775

AC:

AN:

11616

East Asian (EAS)

AF:

0.00134

AC:

AN:

24706

South Asian (SAS)

AF:

0.000992

AC:

AN:

39324

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

21794

Middle Eastern (MID)

AF:

0.00966

AC:

AN:

1656

European-Non Finnish (NFE)

AF:

0.00145

AC:

306

AN:

211608

Other (OTH)

AF:

0.00804

AC:

170

AN:

21140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

125

188

250

313

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:

0.0187

AC:

2815

AN:

150856

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1353

AN XY:

73702

show subpopulations

African (AFR)

AF:

0.0647

AC:

2664

AN:

41176

American (AMR)

AF:

0.00528

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.000626

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.0000970

AC:

AN:

10310

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000414

AC:

AN:

67590

Other (OTH)

AF:

0.0159

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

119

238

356

475

594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0113

Hom.:

Bravo

AF:

0.0205

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.4

(source)

DANN

Benign

0.55

PhyloP100

-1.7

PromoterAI

-0.057

Neutral

(source)

Mutation Taster

=300/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over