rs1371203

Variant names:

• chr2-211819221-G-A
• rs1371203
• NM_005235.3:c.422-31062C>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.422-31062C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 151,942 control chromosomes in the GnomAD database, including 45,555 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 0.77 (45555 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.422-31062C>T		intron_variant	Intron 3 of 27	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.422-31062C>T		intron_variant	Intron 3 of 27	1	NM_005235.3	ENSP00000342235.4

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117417 AN: 151822 Hom.: 45555 Cov.: 32

Gnomad AFR AF: 0.742

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.795

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.773 AC: 117460 AN: 151942 Hom.: 45555 Cov.: 32 AF XY: 0.773 AC XY: 57392 AN XY: 74260

African (AFR) AF: 0.741 AC: 30741 AN: 41462

American (AMR) AF: 0.759 AC: 11565 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2289 AN: 3472

East Asian (EAS) AF: 0.736 AC: 3807 AN: 5174

South Asian (SAS) AF: 0.761 AC: 3660 AN: 4812

European-Finnish (FIN) AF: 0.829 AC: 8761 AN: 10564

Middle Eastern (MID) AF: 0.757 AC: 221 AN: 292

European-Non Finnish (NFE) AF: 0.795 AC: 54007 AN: 67900

Other (OTH) AF: 0.775 AC: 1640 AN: 2116

Alfa AF: 0.785 Hom.: 69145

Bravo AF: 0.763

Asia WGS AF: 0.712 AC: 2469 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.5
DANN	Benign	0.36
PhyloP100		0.11
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: rs1371203; hg19: chr2-212683946;