rs397514262

chr2-211424241-C-Achr2-211424241-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_005235.3(ERBB4):c.2780G>T(p.Arg927Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R927Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERBB4 NM_005235.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity ERBB4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005235.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-211424241-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 64625.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB4	NM_005235.3	c.2780G>T	p.Arg927Leu	missense_variant	23/28	ENST00000342788.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB4	ENST00000342788.9	c.2780G>T	p.Arg927Leu	missense_variant	23/28	1	NM_005235.3	P4
ERBB4	ENST00000436443.5	c.2780G>T	p.Arg927Leu	missense_variant	23/27	1		A1
ERBB4	ENST00000260943.11	c.2750G>T	p.Arg917Leu	missense_variant	23/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
REVEL	Uncertain	0.47
Polyphen		0.80, 0.76	.;P;P
Vest4		0.85, 0.84
MutPred		0.48		.;Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.98
MPC		0.51
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.96
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-212288966;