Variant 19-18933023-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004838.4(HOMER3):c.434G>A(p.Ser145Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000747 in 1,338,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

HOMER3
NM_004838.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.16

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2911595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOMER3	NM_004838.4 linkuse as main transcript	c.434G>A	p.Ser145Asn	missense_variant	6/10	ENST00000392351.8	NP_004829.3	Q9NSC5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOMER3	ENST00000392351.8 linkuse as main transcript	c.434G>A	p.Ser145Asn	missense_variant	6/10	1	NM_004838.4	ENSP00000376162.2		Q9NSC5-1
ENSG00000268193	ENST00000596918.5 linkuse as main transcript	n.116G>A		non_coding_transcript_exon_variant	2/7	5		ENSP00000469669.1		M0R1B8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.47e-7

AC:

AN:

1338302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660680

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000316

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Keratoconus 5

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Refractive Surgery Department, Bright Eye Hospital

May 16, 2024

HOMER is a scaffolding protein and has been largely investigated in the nervous system. This protein has several splice variants and three subtypes (HOMER1, HOMER2, and HOMER3).8 The function and role of HOMER in corneal disease have also been studied. In 2021, Català et al.9 identified the expression of HOMER3 in the corneal epithelium and the limbus. The HOMER family plays an important role in cell function. HOMER3 is such a cytosolic adaptor to involve in the regulation of G protein-coupled receptors.10 The imbalance of the HOMER involved activities is closely related to the development of KC.11-13 In this study, a heterozygous HOMER3 mutation g.19043832C>T (c.434G>A) was detected in family 1, which is located in exon 6, causing a p.G235R amino acid change, and is predicted as highly conserved among species and probably damaging using online software. To date, it is the first time to detect a HOMER3 mutation in a KC family. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.073

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;.;.;.;D;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.29

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L;L;.;L;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.048

Sift

Uncertain

0.018

D;.;D;D;.;D;.;.

Sift4G

Benign

0.30

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

Polyphen

0.80

P;P;P;P;.;P;.;.

Vest4

0.48

MutPred

0.23

Loss of glycosylation at S145 (P = 0.0364);Loss of glycosylation at S145 (P = 0.0364);Loss of glycosylation at S145 (P = 0.0364);Loss of glycosylation at S145 (P = 0.0364);.;Loss of glycosylation at S145 (P = 0.0364);Loss of glycosylation at S145 (P = 0.0364);Loss of glycosylation at S145 (P = 0.0364);

MVP

0.49

MPC

1.3

ClinPred

0.94

GERP RS

4.9

Varity_R

0.29

gMVP

0.34

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over