Genetic Variant NM_005235.3:c.557-6419G>A (chr2-211757123-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005235.3(ERBB4):c.557-6419G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,030 control chromosomes in the GnomAD database, including 7,351 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 7351 hom., cov: 32)

Consequence

ERBB4
NM_005235.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00200

Publications

4 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3 link	c.557-6419G>A		intron_variant	Intron 4 of 27	ENST00000342788.9	NP_005226.1	Q15303-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9 link	c.557-6419G>A		intron_variant	Intron 4 of 27	1	NM_005235.3	ENSP00000342235.4		Q15303-1

Frequencies

GnomAD3 genomes

AF:

0.291

AC:

44273

AN:

151912

Hom.:

7357

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.426

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.00694

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.337

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.291

AC:

44269

AN:

152030

Hom.:

7351

Cov.:

AF XY:

0.287

AC XY:

21351

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.172

AC:

7126

AN:

41500

American (AMR)

AF:

0.319

AC:

4865

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1184

AN:

3468

East Asian (EAS)

AF:

0.00715

AC:

AN:

5176

South Asian (SAS)

AF:

0.158

AC:

764

AN:

4822

European-Finnish (FIN)

AF:

0.363

AC:

3822

AN:

10526

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.372

AC:

25272

AN:

67964

Other (OTH)

AF:

0.333

AC:

701

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1534

3069

4603

6138

7672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.312

Hom.:

6708

Bravo

AF:

0.282

Asia WGS

AF:

0.0900

AC:

313

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.30

(source)

DANN

Benign

0.27

PhyloP100

0.0020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over