rs13030304

Variant names:

• chr2-211418421-C-A
• rs13030304
• NM_005235.3:c.3135+2020G>T

Variant summary

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

The NM_005235.3(ERBB4):​c.3135+2020G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,042 control chromosomes in the GnomAD database, including 2,570 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 0.17 (2570 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.749
• Publications: 7 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	NM_005235.3	MANE Select	c.3135+2020G>T		intron	N/A	NP_005226.1
	ERBB4	NM_001439005.1		c.3105+2020G>T		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.3135+2020G>T		intron	N/A	NP_001036064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.3135+2020G>T		intron	N/A	ENSP00000342235.4
	ERBB4	ENST00000436443.5	TSL:1	c.3135+2020G>T		intron	N/A	ENSP00000403204.1
	ERBB4	ENST00000260943.11	TSL:5	c.3105+2020G>T		intron	N/A	ENSP00000260943.7

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25279 AN: 151924 Hom.: 2569 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.173

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

GnomAD4 genome AF: 0.166 AC: 25277 AN: 152042 Hom.: 2570 Cov.: 32 AF XY: 0.166 AC XY: 12338 AN XY: 74298

African (AFR) AF: 0.0636 AC: 2642 AN: 41540

American (AMR) AF: 0.201 AC: 3072 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3468

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5174

South Asian (SAS) AF: 0.0847 AC: 408 AN: 4816

European-Finnish (FIN) AF: 0.242 AC: 2548 AN: 10544

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15145 AN: 67914

Other (OTH) AF: 0.170 AC: 360 AN: 2112

Alfa AF: 0.207 Hom.: 6213

Bravo AF: 0.160

Asia WGS AF: 0.0590 AC: 206 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.57
DANN	Benign	0.52
PhyloP100		-0.75
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: rs13030304; hg19: chr2-212283146;