NM_005235.3:c.83-175619G>T

Variant names:

• chr2-212300522-C-A
• rs13392330
• NM_005235.3:c.83-175619G>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.83-175619G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 151,242 control chromosomes in the GnomAD database, including 50,423 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 0.80 (50423 hom., cov: 31)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.355
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.83-175619G>T		intron_variant	Intron 1 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.83-175619G>T		intron_variant	Intron 1 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.804 AC: 121559 AN: 151122 Hom.: 50414 Cov.: 31

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.871

Gnomad EAS AF: 0.877

Gnomad SAS AF: 0.798

Gnomad FIN AF: 0.896

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.823

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

GnomAD4 genome AF: 0.804 AC: 121616 AN: 151242 Hom.: 50423 Cov.: 31 AF XY: 0.804 AC XY: 59429 AN XY: 73912

African (AFR) AF: 0.582 AC: 24055 AN: 41316

American (AMR) AF: 0.859 AC: 13002 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 3005 AN: 3452

East Asian (EAS) AF: 0.877 AC: 4487 AN: 5114

South Asian (SAS) AF: 0.798 AC: 3842 AN: 4816

European-Finnish (FIN) AF: 0.896 AC: 9474 AN: 10572

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 60870 AN: 67532

Other (OTH) AF: 0.824 AC: 1732 AN: 2102

Alfa AF: 0.864 Hom.: 18655

Bravo AF: 0.793

Asia WGS AF: 0.814 AC: 2828 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.42
PhyloP100		-0.35
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: rs13392330; hg19: chr2-213165247;