chr19-18931989-C-T

Position:

• chr19-18931989-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004838.4(HOMER3):​c.677G>A​(p.Arg226Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,537,686 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: HOMER3 NM_004838.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008442223).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOMER3	NM_004838.4	c.677G>A	p.Arg226Gln	missense_variant	7/10	ENST00000392351.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOMER3	ENST00000392351.8	c.677G>A	p.Arg226Gln	missense_variant	7/10	1	NM_004838.4	P4

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 151924 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00105 AC: 151 AN: 143730 Hom.: 1 AF XY: 0.00105 AC XY: 81 AN XY: 76950

Gnomad AFR exome AF: 0.000268

Gnomad AMR exome AF: 0.000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000958

Gnomad SAS exome AF: 0.000631

Gnomad FIN exome AF: 0.0000724

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00165 AC: 2290 AN: 1385644 Hom.: 4 Cov.: 34 AF XY: 0.00166 AC XY: 1136 AN XY: 682302

Gnomad4 AFR exome AF: 0.000160

Gnomad4 AMR exome AF: 0.000720

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000109

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 79 AN XY: 74360

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00105

ExAC AF: 0.000480 AC: 44

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.677G>A (p.R226Q) alteration is located in exon 7 (coding exon 6) of the HOMER3 gene. This alteration results from a G to A substitution at nucleotide position 677, causing the arginine (R) at amino acid position 226 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	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;.;T;T;.;.;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.95	D;.;.;.;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;L;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N;.;N;N;.;.;N;.
REVEL	Benign	0.028
Sift	Benign	0.14	T;.;T;T;.;.;T;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T;.
Polyphen		0.87	P;P;P;P;.;.;P;.
Vest4		0.36
MVP		0.25
MPC		0.53
ClinPred		0.017	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs74906645; hg19: chr19-19042798; COSMIC: COSV99651253; COSMIC: COSV99651253;