2-211383725-G-C

Variant names:

• chr2-211383725-G-C
• rs1480034665
• NM_005235.3:c.3817C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005235.3(ERBB4):​c.3817C>G​(p.Arg1273Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1273W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERBB4 NM_005235.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24
• 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005235.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB4	NM_005235.3	c.3817C>G	p.Arg1273Gly	missense_variant	Exon 28 of 28	ENST00000342788.9	NP_005226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB4	ENST00000342788.9	c.3817C>G	p.Arg1273Gly	missense_variant	Exon 28 of 28	1	NM_005235.3	ENSP00000342235.4
ERBB4	ENST00000436443.5	c.3769C>G	p.Arg1257Gly	missense_variant	Exon 27 of 27	1		ENSP00000403204.1
ERBB4	ENST00000260943.11	c.3739C>G	p.Arg1247Gly	missense_variant	Exon 27 of 27	5		ENSP00000260943.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;D;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.6	.;L;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.2	.;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.33	.;T;T
Sift4G	Benign	0.33	.;T;T
Polyphen		0.80, 0.87	.;P;P
Vest4		0.75, 0.71
MutPred		0.41		.;Loss of MoRF binding (P = 0.0456);.;
MVP		0.95
MPC		0.51
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.27
gMVP		0.73
Mutation Taster		=42/58	disease causing

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: rs1480034665; hg19: chr2-212248450;