19-18929578-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004838.4(HOMER3):c.951C>A(p.Ser317Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,545,830 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HOMER3
NM_004838.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.401

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]

HOMER3 links:

ENSG00000268193 (HGNC:):

ENSG00000268193 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.070232034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOMER3	NM_004838.4 link	c.951C>A	p.Ser317Arg	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
HOMER3	ENST00000392351.8 link	c.951C>A	p.Ser317Arg	missense_variant	Exon 10 of 10	1	NM_004838.4	ENSP00000376162.2		Q9NSC5-1
ENSG00000268193	ENST00000596918.5 link	n.*167+1747C>A		intron_variant	Intron 4 of 6	5		ENSP00000469669.1		M0R1B8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000209

AC:

AN:

143620

Hom.:

AF XY:

0.0000257

AC XY:

AN XY:

77932

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000570

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1393582

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

687046

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:

0.0000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.951C>A (p.S317R) alteration is located in exon 10 (coding exon 9) of the HOMER3 gene. This alteration results from a C to A substitution at nucleotide position 951, causing the serine (S) at amino acid position 317 to be replaced by an arginine (R). 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

0.23

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.044

.;.;T;T;.;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.71

T;.;.;.;T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.070

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.29

.;.;N;N;.;.;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.62

N;.;N;N;.;.;N

REVEL

Benign

0.034

Sift

Benign

0.78

T;.;T;T;.;.;T

Sift4G

Benign

0.78

T;T;T;T;T;T;T

Polyphen

0.49

P;P;B;B;.;.;B

Vest4

0.097

MutPred

0.18

.;.;Loss of phosphorylation at S317 (P = 0.0024);Loss of phosphorylation at S317 (P = 0.0024);.;.;Loss of phosphorylation at S317 (P = 0.0024);

MVP

0.16

MPC

0.51

ClinPred

0.038

GERP RS

1.9

Varity_R

0.11

gMVP

0.24

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over