2-211383653-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005235.3(ERBB4):​c.3889C>T​(p.Pro1297Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ERBB4
NM_005235.3 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERBB4NM_005235.3 linkc.3889C>T p.Pro1297Ser 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.3889C>T p.Pro1297Ser missense_variant Exon 28 of 28 1 NM_005235.3 ENSP00000342235.4 Q15303-1
ERBB4ENST00000436443.5 linkc.3841C>T p.Pro1281Ser missense_variant Exon 27 of 27 1 ENSP00000403204.1 Q15303-3
ERBB4ENST00000260943.11 linkc.3811C>T p.Pro1271Ser missense_variant Exon 27 of 27 5 ENSP00000260943.7 Q15303-4H3BLT0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461538
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1297 of the ERBB4 protein (p.Pro1297Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ERBB4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
T;D;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Uncertain
0.63
D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Benign
1.9
.;L;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-2.3
.;N;N
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
.;D;D
Sift4G
Uncertain
0.022
.;D;D
Polyphen
1.0
.;D;D
Vest4
0.38, 0.41
MutPred
0.24
.;Loss of catalytic residue at P1297 (P = 0.0018);.;
MVP
0.82
MPC
1.1
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.42
gMVP
0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1279524244; hg19: chr2-212248378; COSMIC: COSV61507863; API