chr19-18929504-C-T

Variant names:

• chr19-18929504-C-T
• NM_004838.4:c.1025G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004838.4(HOMER3):​c.1025G>A​(p.Ser342Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 0 publications found

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]

ENSG00000268193 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09940103).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOMER3	NM_004838.4	MANE Select	c.1025G>A	p.Ser342Asn	missense	Exon 10 of 10	NP_004829.3
	HOMER3	NM_001145722.2		c.1025G>A	p.Ser342Asn	missense	Exon 10 of 10	NP_001139194.1	Q9NSC5-1
	HOMER3	NM_001145721.1		c.1016G>A	p.Ser339Asn	missense	Exon 10 of 10	NP_001139193.1	Q9NSC5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HOMER3	ENST00000392351.8	TSL:1 MANE Select	c.1025G>A	p.Ser342Asn	missense	Exon 10 of 10	ENSP00000376162.2	Q9NSC5-1
	HOMER3	ENST00000539827.5	TSL:1	c.1025G>A	p.Ser342Asn	missense	Exon 9 of 9	ENSP00000439937.1	Q9NSC5-1
	HOMER3	ENST00000542541.6	TSL:1	c.1025G>A	p.Ser342Asn	missense	Exon 10 of 10	ENSP00000446026.1	Q9NSC5-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.066	B
Vest4		0.063
MutPred		0.18		Loss of phosphorylation at S342 (P = 0.0284)
MVP		0.19
MPC		0.45
ClinPred		0.46	T
GERP RS		2.8
Varity_R		0.60
gMVP		0.34
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr19-19040313;