2-211383647-G-C

Variant names:

Variant summary

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

The NM_005235.3(ERBB4):c.3895C>G(p.Pro1299Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ERBB4
NM_005235.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.37

Publications

1 publications found

Variant links:

Genes affected

ERBB4 (HGNC:3432): (erb-b2 receptor tyrosine kinase 4) This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ERBB4 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 19
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ERBB4 links:

Genome browser will be placed here

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3 link	c.3895C>G	p.Pro1299Ala	missense_variant	Exon 28 of 28	ENST00000342788.9	NP_005226.1	Q15303-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERBB4	ENST00000342788.9 link	c.3895C>G	p.Pro1299Ala	missense_variant	Exon 28 of 28	1	NM_005235.3	ENSP00000342235.4	Q15303-1
ERBB4	ENST00000436443.5 link	c.3847C>G	p.Pro1283Ala	missense_variant	Exon 27 of 27	1		ENSP00000403204.1	Q15303-3
ERBB4	ENST00000260943.11 link	c.3817C>G	p.Pro1273Ala	missense_variant	Exon 27 of 27	5		ENSP00000260943.7	Q15303-4H3BLT0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251162

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3895C>G (p.P1299A) alteration is located in exon 28 (coding exon 28) of the ERBB4 gene. This alteration results from a C to G substitution at nucleotide position 3895, causing the proline (P) at amino acid position 1299 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.8

.;L;.

PhyloP100

9.4

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

.;N;N

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

.;D;D

Polyphen

1.0

.;D;D

Vest4

0.36, 0.44

MutPred

0.31

.;Loss of glycosylation at P1299 (P = 0.006);.;

MVP

0.80

MPC

1.0

ClinPred

0.97

GERP RS

5.4

Varity_R

0.42

gMVP

0.53

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over