Variant 19-18932040-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004838.4(HOMER3):c.626C>G(p.Ala209Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

HOMER3
NM_004838.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.911

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16649985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOMER3	NM_004838.4 link	c.626C>G	p.Ala209Gly	missense_variant	Exon 7 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.626C>G	p.Ala209Gly	missense_variant	Exon 7 of 10	1	NM_004838.4	ENSP00000376162.2		Q9NSC5-1
ENSG00000268193	ENST00000596918.5 link	n.216-415C>G		intron_variant	Intron 2 of 6	5		ENSP00000469669.1		M0R1B8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.626C>G (p.A209G) alteration is located in exon 7 (coding exon 6) of the HOMER3 gene. This alteration results from a C to G substitution at nucleotide position 626, causing the alanine (A) at amino acid position 209 to be replaced by a glycine (G). 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

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.094

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

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.0090

MetaRNN

Benign

0.17

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.21

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

REVEL

Benign

0.050

Sift

Benign

0.098

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

Sift4G

Benign

0.17

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

Polyphen

0.65

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

Vest4

0.30

MutPred

0.35

Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);.;Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);

MVP

0.14

MPC

1.3

ClinPred

0.69

GERP RS

1.6

Varity_R

0.11

gMVP

0.15

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