Genetic Variant ERBB3:c.3202-101_3202-97dupAAAAA (chr12-56100939-C-CAAAAA) – 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.3202-101_3202-97dupAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 303,614 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 0.000079 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000075 ( 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:

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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.3202-101_3202-97dupAAAAA	intron_variant	Intron 26 of 27	ENST00000267101.8	NP_001973.2	P21860-1
ERBB3	XM_047428500.1 link	c.3025-101_3025-97dupAAAAA	intron_variant	Intron 26 of 27		XP_047284456.1
ERBB3	XM_047428501.1 link	c.3025-101_3025-97dupAAAAA	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_3202-121insAAAAA		intron_variant	Intron 26 of 27	1	NM_001982.4	ENSP00000267101.4		P21860-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

50666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000908

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.000609

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:

0.0000751

AC:

AN:

252956

Hom.:

AF XY:

0.0000779

AC XY:

AN XY:

141220

show subpopulations

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

African (AFR)

AF:

0.000495

AC:

AN:

6058

American (AMR)

AF:

0.0000693

AC:

AN:

14430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7504

East Asian (EAS)

AF:

0.0000925

AC:

AN:

10808

South Asian (SAS)

AF:

0.0000456

AC:

AN:

43828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

838

European-Non Finnish (NFE)

AF:

0.0000821

AC:

AN:

146142

Other (OTH)

AF:

0.00

AC:

AN:

12142

⚠️ 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: 0.267

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:

0.0000790

AC:

AN:

50658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22164

show subpopulations

African (AFR)

AF:

0.0000908

AC:

AN:

11016

American (AMR)

AF:

0.000263

AC:

AN:

3804

Ashkenazi Jewish (ASJ)

AF:

0.000609

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:

624

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: 0.488

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-CAAAAAAAAAAAAAAAAAAAAA

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