19-18929528-C-T

Variant names:

• chr19-18929528-C-T
• rs769140408
• NM_004838.4:c.1001G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004838.4(HOMER3):​c.1001G>A​(p.Arg334Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,569,766 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: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: HOMER3 NM_004838.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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

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=0.11640704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HOMER3	NM_004838.4	c.1001G>A	p.Arg334Gln	missense_variant	Exon 10 of 10	ENST00000392351.8	NP_004829.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HOMER3	ENST00000392351.8	c.1001G>A	p.Arg334Gln	missense_variant	Exon 10 of 10	1	NM_004838.4	ENSP00000376162.2
ENSG00000268193	ENST00000596918.5	n.*167+1797G>A		intron_variant	Intron 4 of 6	5		ENSP00000469669.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152258 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000660 AC: 11 AN: 166658 Hom.: 0 AF XY: 0.0000546 AC XY: 5 AN XY: 91508

Gnomad AFR exome AF: 0.000222

Gnomad AMR exome AF: 0.0000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000772

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 58 AN: 1417508 Hom.: 0 Cov.: 43 AF XY: 0.0000399 AC XY: 28 AN XY: 702134

Gnomad4 AFR exome AF: 0.000215

Gnomad4 AMR exome AF: 0.0000507

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000532

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000403

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.0000672 AC XY: 5 AN XY: 74384

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

ExAC AF: 0.0000342 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1001G>A (p.R334Q) alteration is located in exon 10 (coding exon 9) of the HOMER3 gene. This alteration results from a G to A substitution at nucleotide position 1001, causing the arginine (R) at amino acid position 334 to be replaced by a glutamine (Q). 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	0.090
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.54
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.046	.;.;T;T;.;.;T
Eigen	Benign	0.092
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.88	D;.;.;.;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	.;.;L;L;.;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N;.;N;N;.;.;N
REVEL	Benign	0.043
Sift	Benign	0.20	T;.;T;T;.;.;T
Sift4G	Benign	0.29	T;T;T;T;D;T;T
Polyphen		0.99	D;D;D;D;.;.;D
Vest4		0.15
MutPred		0.24		.;.;Loss of methylation at R334 (P = 0.0037);Loss of methylation at R334 (P = 0.0037);.;.;Loss of methylation at R334 (P = 0.0037);
MVP		0.25
MPC		1.4
ClinPred		0.070	T
GERP RS		4.0
Varity_R		0.35
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs769140408; hg19: chr19-19040337; COSMIC: COSV55356208; COSMIC: COSV55356208;