rs1816532

Variant names:

• chr2-211403515-A-C
• rs1816532
• NM_005235.3:c.3136-15523T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005235.3(ERBB4):​c.3136-15523T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 151,954 control chromosomes in the GnomAD database, including 5,749 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 0.27 (5749 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• Publications: 8 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.3136-15523T>G		intron	N/A	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.3106-15523T>G		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.3136-16365T>G		intron	N/A	NP_001036064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.3136-15523T>G		intron	N/A	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.3136-16365T>G		intron	N/A	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000260943.11	TSL:5	c.3106-16365T>G		intron	N/A	ENSP00000260943.7	Q15303-4

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41081 AN: 151838 Hom.: 5750 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.270 AC: 41082 AN: 151954 Hom.: 5749 Cov.: 32 AF XY: 0.268 AC XY: 19903 AN XY: 74274

African (AFR) AF: 0.213 AC: 8839 AN: 41454

American (AMR) AF: 0.267 AC: 4067 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3472

East Asian (EAS) AF: 0.392 AC: 2019 AN: 5156

South Asian (SAS) AF: 0.205 AC: 984 AN: 4800

European-Finnish (FIN) AF: 0.288 AC: 3048 AN: 10582

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20162 AN: 67946

Other (OTH) AF: 0.260 AC: 547 AN: 2106

Alfa AF: 0.285 Hom.: 3436

Bravo AF: 0.269

Asia WGS AF: 0.250 AC: 870 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.72
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1816532; hg19: chr2-212268240;