Genetic Variant ERBB3:c.3202-106_3202-97delAAAAAAAAAA (chr12-56100939-CAAAAAAAAAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001982.4(ERBB3):c.3202-106_3202-97delAAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 303,720 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 0.000039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ERBB3
NM_001982.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERBB3	NM_001982.4 link	c.3202-106_3202-97delAAAAAAAAAA	intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 link	c.3025-106_3025-97delAAAAAAAAAA	intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1 link	c.3025-106_3025-97delAAAAAAAAAA	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.3202-121_3202-112delAAAAAAAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

50668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000335

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

253060

Hom.:

AF XY:

0.0000142

AC XY:

AN XY:

141258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6070

American (AMR)

AF:

0.000139

AC:

AN:

14440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7504

East Asian (EAS)

AF:

0.00

AC:

AN:

10818

South Asian (SAS)

AF:

0.00

AC:

AN:

43836

European-Finnish (FIN)

AF:

0.0000892

AC:

AN:

11206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

838

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

146202

Other (OTH)

AF:

0.00

AC:

AN:

12146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.0000395

AC:

AN:

50660

Hom.:

Cov.:

AF XY:

0.0000451

AC XY:

AN XY:

22166

show subpopulations

African (AFR)

AF:

0.00

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:

0.0000336

AC:

AN:

29806

Other (OTH)

AF:

0.00

AC:

AN:

696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.700

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Splicing

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

Publications

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12-56100939-CAAAAAAAAAAAAAAAA-CAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over