19-18929508-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004838.4(HOMER3):​c.1021G>A​(p.Val341Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,584,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

HOMER3
NM_004838.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09
Variant links:
Genes affected
HOMER3 (HGNC:17514): (homer scaffold protein 3) This gene encodes a member of the HOMER family of postsynaptic density scaffolding proteins that share a similar domain structure consisting of an N-terminal Enabled/vasodilator-stimulated phosphoprotein homology 1 domain which mediates protein-protein interactions, and a carboxy-terminal coiled-coil domain and two leucine zipper motifs that are involved in self-oligomerization. The encoded protein binds numerous other proteins including group I metabotropic glutamate receptors, inositol 1,4,5-trisphosphate receptors and amyloid precursor proteins and has been implicated in diverse biological functions such as neuronal signaling, T-cell activation and trafficking of amyloid beta peptides. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.053379297).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HOMER3NM_004838.4 linkc.1021G>A p.Val341Ile missense_variant Exon 10 of 10 ENST00000392351.8 NP_004829.3 Q9NSC5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HOMER3ENST00000392351.8 linkc.1021G>A p.Val341Ile missense_variant Exon 10 of 10 1 NM_004838.4 ENSP00000376162.2 Q9NSC5-1
ENSG00000268193ENST00000596918.5 linkn.*167+1817G>A intron_variant Intron 4 of 6 5 ENSP00000469669.1 M0R1B8

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152264
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000208
AC:
4
AN:
191860
Hom.:
0
AF XY:
0.00000944
AC XY:
1
AN XY:
105942
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000114
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000741
Gnomad NFE exome
AF:
0.0000246
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000182
AC:
26
AN:
1431962
Hom.:
0
Cov.:
44
AF XY:
0.0000253
AC XY:
18
AN XY:
710578
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000157
Gnomad4 EAS exome
AF:
0.0000519
Gnomad4 SAS exome
AF:
0.0000360
Gnomad4 FIN exome
AF:
0.0000654
Gnomad4 NFE exome
AF:
0.0000100
Gnomad4 OTH exome
AF:
0.0000506
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152264
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000567

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1021G>A (p.V341I) alteration is located in exon 10 (coding exon 9) of the HOMER3 gene. This alteration results from a G to A substitution at nucleotide position 1021, causing the valine (V) at amino acid position 341 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
20
DANN
Benign
0.84
DEOGEN2
Benign
0.050
.;.;T;T;.;.;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.79
T;.;.;.;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.053
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
.;.;L;L;.;.;L
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.69
N;.;N;N;.;.;N
REVEL
Benign
0.072
Sift
Benign
0.44
T;.;T;T;.;.;T
Sift4G
Benign
0.32
T;T;T;T;T;T;T
Polyphen
0.94
P;P;P;P;.;.;P
Vest4
0.14
MVP
0.13
MPC
1.2
ClinPred
0.11
T
GERP RS
2.9
Varity_R
0.14
gMVP
0.078

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1026416699; hg19: chr19-19040317; API