NM_005235.3:c.83-91815A>C

Variant names:

• chr2-212216718-T-G
• rs1402769
• NM_005235.3:c.83-91815A>C

Variant summary

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

The NM_005235.3(ERBB4):​c.83-91815A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 151,012 control chromosomes in the GnomAD database, including 39,927 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 0.72 (39927 hom., cov: 31)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• Publications: 3 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 (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.83-91815A>C		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.83-91815A>C		intron_variant	Intron 1 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.724 AC: 109235 AN: 150894 Hom.: 39903 Cov.: 31

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.686

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.721

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

GnomAD4 genome AF: 0.724 AC: 109302 AN: 151012 Hom.: 39927 Cov.: 31 AF XY: 0.720 AC XY: 53141 AN XY: 73796

African (AFR) AF: 0.667 AC: 27589 AN: 41356

American (AMR) AF: 0.685 AC: 10327 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2704 AN: 3446

East Asian (EAS) AF: 0.777 AC: 3998 AN: 5144

South Asian (SAS) AF: 0.487 AC: 2342 AN: 4812

European-Finnish (FIN) AF: 0.811 AC: 8569 AN: 10568

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.761 AC: 51223 AN: 67318

Other (OTH) AF: 0.723 AC: 1509 AN: 2086

Alfa AF: 0.740 Hom.: 72877

Bravo AF: 0.718

Asia WGS AF: 0.633 AC: 2202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.90
DANN	Benign	0.50
PhyloP100		-0.44
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: rs1402769; hg19: chr2-213081443;