NM_005235.3:c.3888G>C

Variant names:

• chr2-211383654-C-G
• rs755829219
• NM_005235.3:c.3888G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_005235.3(ERBB4):​c.3888G>C​(p.Leu1296Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1296L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERBB4 NM_005235.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 0 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.

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.3888G>C	p.Leu1296Leu	synonymous	Exon 28 of 28	NP_005226.1	Q15303-1
	ERBB4	NM_001439005.1		c.3858G>C	p.Leu1286Leu	synonymous	Exon 28 of 28	NP_001425934.1
	ERBB4	NM_001042599.2		c.3840G>C	p.Leu1280Leu	synonymous	Exon 27 of 27	NP_001036064.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB4	ENST00000342788.9	TSL:1 MANE Select	c.3888G>C	p.Leu1296Leu	synonymous	Exon 28 of 28	ENSP00000342235.4	Q15303-1
	ERBB4	ENST00000436443.5	TSL:1	c.3840G>C	p.Leu1280Leu	synonymous	Exon 27 of 27	ENSP00000403204.1	Q15303-3
	ERBB4	ENST00000260943.11	TSL:5	c.3810G>C	p.Leu1270Leu	synonymous	Exon 27 of 27	ENSP00000260943.7	Q15303-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.9
DANN	Benign	0.73
PhyloP100		2.4
Mutation Taster		=95/5	polymorphism

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: rs755829219; hg19: chr2-212248379;