chr19-18929528-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004838.4(HOMER3):c.1001G>T(p.Arg334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

HOMER3
NM_004838.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41013286).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004838.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOMER3	NM_004838.4	MANE Select	c.1001G>T	p.Arg334Leu	missense	Exon 10 of 10	NP_004829.3
HOMER3	NM_001145722.2		c.1001G>T	p.Arg334Leu	missense	Exon 10 of 10	NP_001139194.1	Q9NSC5-1
HOMER3	NM_001145721.1		c.992G>T	p.Arg331Leu	missense	Exon 10 of 10	NP_001139193.1	Q9NSC5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HOMER3	ENST00000392351.8	TSL:1 MANE Select	c.1001G>T	p.Arg334Leu	missense	Exon 10 of 10	ENSP00000376162.2	Q9NSC5-1
HOMER3	ENST00000539827.5	TSL:1	c.1001G>T	p.Arg334Leu	missense	Exon 9 of 9	ENSP00000439937.1	Q9NSC5-1
HOMER3	ENST00000542541.6	TSL:1	c.1001G>T	p.Arg334Leu	missense	Exon 10 of 10	ENSP00000446026.1	Q9NSC5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1417512

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702134

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32560

American (AMR)

AF:

0.00

AC:

AN:

39452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25358

East Asian (EAS)

AF:

0.00

AC:

AN:

37562

South Asian (SAS)

AF:

0.00

AC:

AN:

81914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5068

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091830

Other (OTH)

AF:

0.00

AC:

AN:

58726

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

M_CAP

Benign

0.044

MetaRNN

Benign

0.41

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

2.0

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.065

Sift

Benign

0.13

Sift4G

Benign

0.19

Polyphen

0.95

Vest4

0.52

MutPred

0.34

Loss of methylation at R334 (P = 0.0037)

MVP

0.33

MPC

1.5

ClinPred

0.93

GERP RS

4.0

Varity_R

0.46

gMVP

0.39

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over