19-18929574-C-T

Variant names:

• chr19-18929574-C-T
• rs1296258668
• NM_004838.4:c.955G>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.955G>A​(p.Glu319Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,547,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E319Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: HOMER3 NM_004838.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• Publications: 1 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=0.18744606).

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.955G>A	p.Glu319Lys	missense	Exon 10 of 10	NP_004829.3
	HOMER3	NM_001145722.2		c.955G>A	p.Glu319Lys	missense	Exon 10 of 10	NP_001139194.1	Q9NSC5-1
	HOMER3	NM_001145721.1		c.946G>A	p.Glu316Lys	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.955G>A	p.Glu319Lys	missense	Exon 10 of 10	ENSP00000376162.2	Q9NSC5-1
	HOMER3	ENST00000539827.5	TSL:1	c.955G>A	p.Glu319Lys	missense	Exon 9 of 9	ENSP00000439937.1	Q9NSC5-1
	HOMER3	ENST00000542541.6	TSL:1	c.955G>A	p.Glu319Lys	missense	Exon 10 of 10	ENSP00000446026.1	Q9NSC5-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152268 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000694 AC: 1 AN: 144190 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395324 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 688226

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

African (AFR) AF: 0.00 AC: 0 AN: 31776

American (AMR) AF: 0.00 AC: 0 AN: 35914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25100

East Asian (EAS) AF: 0.00 AC: 0 AN: 36090

South Asian (SAS) AF: 0.00 AC: 0 AN: 79478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4780

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078846

Other (OTH) AF: 0.00 AC: 0 AN: 57830

⚠️ 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.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152268 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.032
Sift	Benign	0.031	D
Sift4G	Benign	0.17	T
Polyphen		0.37	B
Vest4		0.26
MutPred		0.32		Gain of MoRF binding (P = 0.0067)
MVP		0.35
MPC		1.4
ClinPred		0.60	D
GERP RS		4.0
Varity_R		0.32
gMVP		0.22
Mutation Taster		=81/19	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: rs1296258668; hg19: chr19-19040383;