rs10203750

Variant names:

• chr2-211821543-T-A
• rs10203750
• NM_005235.3:c.422-33384A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-211821543-T-A
• chr2-211821543-T-C
• chr2-211821543-T-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.422-33384A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.842 in 151,942 control chromosomes in the GnomAD database, including 53,986 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 0.84 (53986 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.545
• Publications: 1 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.858 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.422-33384A>T		intron	N/A	NP_005226.1
	ERBB4	NM_001439005.1		c.422-33384A>T		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.422-33384A>T		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.422-33384A>T		intron	N/A	ENSP00000342235.4
	ERBB4	ENST00000436443.5	TSL:1	c.422-33384A>T		intron	N/A	ENSP00000403204.1
	ERBB4	ENST00000484594.5	TSL:1	n.474-33384A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.842 AC: 127838 AN: 151824 Hom.: 53959 Cov.: 32

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.917

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.841

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

GnomAD4 genome AF: 0.842 AC: 127917 AN: 151942 Hom.: 53986 Cov.: 32 AF XY: 0.840 AC XY: 62396 AN XY: 74240

African (AFR) AF: 0.827 AC: 34310 AN: 41496

American (AMR) AF: 0.809 AC: 12307 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2947 AN: 3470

East Asian (EAS) AF: 0.744 AC: 3835 AN: 5158

South Asian (SAS) AF: 0.807 AC: 3892 AN: 4822

European-Finnish (FIN) AF: 0.864 AC: 9149 AN: 10592

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.864 AC: 58627 AN: 67866

Other (OTH) AF: 0.839 AC: 1772 AN: 2112

Alfa AF: 0.855 Hom.: 6928

Bravo AF: 0.835

Asia WGS AF: 0.752 AC: 2615 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.0
DANN	Benign	0.55
PhyloP100		-0.55
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: rs10203750; hg19: chr2-212686268;