Genetic Variant ERBB3:c.3202-100_3202-97dupAAAA (chr12-56100939-C-CAAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001982.4(ERBB3):c.3202-100_3202-97dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 303,448 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

ERBB3
NM_001982.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0110

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.3202-100_3202-97dupAAAA	intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 link	c.3025-100_3025-97dupAAAA	intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1 link	c.3025-100_3025-97dupAAAA	intron_variant	Intron 26 of 27		XP_047284457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB3	ENST00000267101.8 link	c.3202-122_3202-121insAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

50664

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000182

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000201

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000257

AC:

AN:

252792

Hom.:

AF XY:

0.000276

AC XY:

AN XY:

141106

show subpopulations

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

African (AFR)

AF:

0.000661

AC:

AN:

6056

American (AMR)

AF:

0.000347

AC:

AN:

14428

Ashkenazi Jewish (ASJ)

AF:

0.000401

AC:

AN:

7488

East Asian (EAS)

AF:

0.000370

AC:

AN:

10800

South Asian (SAS)

AF:

0.000205

AC:

AN:

43800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

838

European-Non Finnish (NFE)

AF:

0.000260

AC:

AN:

146054

Other (OTH)

AF:

0.000165

AC:

AN:

12128

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000178

AC:

AN:

50656

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

22164

show subpopulations

African (AFR)

AF:

0.000182

AC:

AN:

11016

American (AMR)

AF:

0.000263

AC:

AN:

3804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1642

East Asian (EAS)

AF:

0.00

AC:

AN:

1534

South Asian (SAS)

AF:

0.00

AC:

AN:

996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000201

AC:

AN:

29802

Other (OTH)

AF:

0.00

AC:

AN:

696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.403

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.011

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAAAA

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