rs545302445

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005235.3(ERBB4):​c.3878G>T​(p.Gly1293Val) 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.

Frequency

Genomes: not found (cov: 32)

Consequence

ERBB4
NM_005235.3 missense

Scores

8
7
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.39
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERBB4NM_005235.3 linkc.3878G>T p.Gly1293Val missense_variant Exon 28 of 28 ENST00000342788.9 NP_005226.1 Q15303-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERBB4ENST00000342788.9 linkc.3878G>T p.Gly1293Val missense_variant Exon 28 of 28 1 NM_005235.3 ENSP00000342235.4 Q15303-1
ERBB4ENST00000436443.5 linkc.3830G>T p.Gly1277Val missense_variant Exon 27 of 27 1 ENSP00000403204.1 Q15303-3
ERBB4ENST00000260943.11 linkc.3800G>T p.Gly1267Val missense_variant Exon 27 of 27 5 ENSP00000260943.7 Q15303-4H3BLT0

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
Benign
0.15
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;D;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Benign
1.9
.;L;.
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-2.5
.;D;D
REVEL
Pathogenic
0.69
Sift
Pathogenic
0.0
.;D;D
Sift4G
Uncertain
0.011
.;D;D
Polyphen
1.0
.;D;D
Vest4
0.67, 0.63
MutPred
0.41
.;Loss of disorder (P = 0.0481);.;
MVP
0.86
MPC
1.2
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.73
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: chr2-212248389; API