Variant chr19-18933042-G-A 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.415C>T(p.Pro139Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000299 in 1,336,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

HOMER3
NM_004838.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.44

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:

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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=0.12340081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOMER3	NM_004838.4 linkuse as main transcript	c.415C>T	p.Pro139Ser	missense_variant	6/10	ENST00000392351.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOMER3	ENST00000392351.8 linkuse as main transcript	c.415C>T	p.Pro139Ser	missense_variant	6/10	1	NM_004838.4	P4	Q9NSC5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000132

AC:

AN:

151552

Hom.:

AF XY:

0.0000118

AC XY:

AN XY:

84940

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000810

Gnomad ASJ exome

AF:

0.000195

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000299

AC:

AN:

1336394

Hom.:

Cov.:

AF XY:

0.00000303

AC XY:

AN XY:

659098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000959

Gnomad4 ASJ exome

AF:

0.0000468

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.47e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.415C>T (p.P139S) alteration is located in exon 6 (coding exon 5) of the HOMER3 gene. This alteration results from a C to T substitution at nucleotide position 415, causing the proline (P) at amino acid position 139 to be replaced by a serine (S). 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

0.073

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

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

Eigen

Benign

-0.036

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.79

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

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

REVEL

Benign

0.043

Sift

Benign

0.72

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

Sift4G

Benign

0.20

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

Polyphen

0.0080

B;B;B;B;.;B;.;.

Vest4

0.43

MutPred

0.14

Gain of phosphorylation at P139 (P = 0.0203);Gain of phosphorylation at P139 (P = 0.0203);Gain of phosphorylation at P139 (P = 0.0203);Gain of phosphorylation at P139 (P = 0.0203);.;Gain of phosphorylation at P139 (P = 0.0203);Gain of phosphorylation at P139 (P = 0.0203);Gain of phosphorylation at P139 (P = 0.0203);

MVP

0.42

MPC

0.71

ClinPred

0.73

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.22

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.

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