rs4423543

Variant names:

• chr2-211671321-G-A
• rs4423543
• NM_005235.3:c.1716+1843C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-211671321-G-A
• chr2-211671321-G-C
• chr2-211671321-G-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.1716+1843C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 151,940 control chromosomes in the GnomAD database, including 7,395 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 0.28 (7395 hom., cov: 32)
• Consequence: ERBB4 NM_005235.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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 (EAS) allele frequency at 95% confidence interval = 0.854 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.1716+1843C>T		intron	N/A	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.1716+1843C>T		intron	N/A	NP_001425934.1
	ERBB4	NM_001042599.2		c.1716+1843C>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.1716+1843C>T		intron	N/A	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.1716+1843C>T		intron	N/A	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000484594.5	TSL:1	n.1768+1843C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42262 AN: 151822 Hom.: 7388 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.293

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

GnomAD4 genome AF: 0.278 AC: 42292 AN: 151940 Hom.: 7395 Cov.: 32 AF XY: 0.286 AC XY: 21212 AN XY: 74262

African (AFR) AF: 0.160 AC: 6626 AN: 41474

American (AMR) AF: 0.346 AC: 5283 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1298 AN: 3468

East Asian (EAS) AF: 0.875 AC: 4526 AN: 5170

South Asian (SAS) AF: 0.477 AC: 2295 AN: 4816

European-Finnish (FIN) AF: 0.258 AC: 2714 AN: 10526

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18457 AN: 67914

Other (OTH) AF: 0.295 AC: 623 AN: 2110

Alfa AF: 0.273 Hom.: 988

Bravo AF: 0.282

Asia WGS AF: 0.665 AC: 2295 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.54
DANN	Benign	0.17
PhyloP100		-0.53
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: rs4423543; hg19: chr2-212536046;