NM_005235.3:c.3135+63A>G

Variant names:

Variant summary

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

The NM_005235.3(ERBB4):c.3135+63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,174,814 control chromosomes in the GnomAD database, including 87,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13431 hom., cov: 32)

Exomes 𝑓: 0.37 ( 74108 hom. )

Consequence

ERBB4
NM_005235.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.57

Publications

16 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-211420378-T-C is Benign according to our data. Variant chr2-211420378-T-C is described in ClinVar as Benign. ClinVar VariationId is 1283533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ERBB4	NM_005235.3	MANE Select	c.3135+63A>G	intron	N/A	NP_005226.1
ERBB4	NM_001439005.1		c.3105+63A>G	intron	N/A	NP_001425934.1
ERBB4	NM_001042599.2		c.3135+63A>G	intron	N/A	NP_001036064.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.3135+63A>G	intron	N/A	ENSP00000342235.4
ERBB4	ENST00000436443.5	TSL:1	c.3135+63A>G	intron	N/A	ENSP00000403204.1
ERBB4	ENST00000260943.11	TSL:5	c.3105+63A>G	intron	N/A	ENSP00000260943.7

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

61945

AN:

151702

Hom.:

13395

Cov.:

show subpopulations

Gnomad AFR

AF:

0.541

Gnomad AMI

AF:

0.287

Gnomad AMR

AF:

0.399

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.449

Gnomad SAS

AF:

0.566

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.345

Gnomad OTH

AF:

0.386

GnomAD4 exome

AF:

0.373

AC:

381310

AN:

1022994

Hom.:

74108

AF XY:

0.379

AC XY:

198245

AN XY:

523538

show subpopulations

African (AFR)

AF:

0.547

AC:

13209

AN:

24140

American (AMR)

AF:

0.422

AC:

16431

AN:

38896

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

7127

AN:

22956

East Asian (EAS)

AF:

0.494

AC:

17165

AN:

34772

South Asian (SAS)

AF:

0.561

AC:

41340

AN:

73684

European-Finnish (FIN)

AF:

0.287

AC:

14242

AN:

49656

Middle Eastern (MID)

AF:

0.393

AC:

1376

AN:

3500

European-Non Finnish (NFE)

AF:

0.347

AC:

253602

AN:

730134

Other (OTH)

AF:

0.372

AC:

16818

AN:

45256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

11789

23578

35367

47156

58945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7090

14180

21270

28360

35450

<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:

0.409

AC:

62045

AN:

151820

Hom.:

13431

Cov.:

AF XY:

0.409

AC XY:

30382

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.542

AC:

22460

AN:

41448

American (AMR)

AF:

0.399

AC:

6078

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1001

AN:

3466

East Asian (EAS)

AF:

0.449

AC:

2310

AN:

5148

South Asian (SAS)

AF:

0.567

AC:

2736

AN:

4824

European-Finnish (FIN)

AF:

0.271

AC:

2866

AN:

10566

Middle Eastern (MID)

AF:

0.390

AC:

114

AN:

292

European-Non Finnish (NFE)

AF:

0.345

AC:

23402

AN:

67822

Other (OTH)

AF:

0.387

AC:

816

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1793

3586

5378

7171

8964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

590

1180

1770

2360

2950

<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:

0.372

Hom.:

4528

Bravo

AF:

0.421

Asia WGS

AF:

0.513

AC:

1781

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

May 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 63. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.042

(source)

DANN

Benign

0.55

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over