19-18931343-C-G

Variant names:

• chr19-18931343-C-G
• rs201061023
• NM_004838.4:c.876G>C

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.876G>C​(p.Glu292Asp) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HOMER3 NM_004838.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• 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=0.12963301).

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.876G>C	p.Glu292Asp	missense	Exon 9 of 10	NP_004829.3
	HOMER3	NM_001145722.2		c.876G>C	p.Glu292Asp	missense	Exon 9 of 10	NP_001139194.1	Q9NSC5-1
	HOMER3	NM_001145721.1		c.876G>C	p.Glu292Asp	missense	Exon 9 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.876G>C	p.Glu292Asp	missense	Exon 9 of 10	ENSP00000376162.2	Q9NSC5-1
	HOMER3	ENST00000539827.5	TSL:1	c.876G>C	p.Glu292Asp	missense	Exon 8 of 9	ENSP00000439937.1	Q9NSC5-1
	HOMER3	ENST00000542541.6	TSL:1	c.876G>C	p.Glu292Asp	missense	Exon 9 of 10	ENSP00000446026.1	Q9NSC5-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.55
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.13
Sift	Benign	0.066	T
Sift4G	Benign	0.32	T
Polyphen		0.99	D
Vest4		0.33
MutPred		0.052		Loss of helix (P = 0.0795)
MVP		0.36
MPC		0.41
ClinPred		0.28	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.17
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs201061023; hg19: chr19-19042152;