chr19-18932040-G-C

Position:

• chr19-18932040-G-C

Variant summary

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

The NM_004838.4(HOMER3):​c.626C>G​(p.Ala209Gly) 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. 13/21 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: 0.911

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 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=0.16649985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOMER3	NM_004838.4	c.626C>G	p.Ala209Gly	missense_variant	7/10	ENST00000392351.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOMER3	ENST00000392351.8	c.626C>G	p.Ala209Gly	missense_variant	7/10	1	NM_004838.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

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

Feb 06, 2024

The c.626C>G (p.A209G) alteration is located in exon 7 (coding exon 6) of the HOMER3 gene. This alteration results from a C to G substitution at nucleotide position 626, causing the alanine (A) at amino acid position 209 to be replaced by a glycine (G). 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	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	.;.;T;T;.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.82	T;.;.;.;T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.21	N;.;N;N;.;N;.
REVEL	Benign	0.050
Sift	Benign	0.098	T;.;T;T;.;T;.
Sift4G	Benign	0.17	T;T;T;T;T;T;.
Polyphen		0.65	P;P;P;P;.;P;.
Vest4		0.30
MutPred		0.35		Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);.;Loss of stability (P = 0.0888);Loss of stability (P = 0.0888);
MVP		0.14
MPC		1.3
ClinPred		0.69	D
GERP RS		1.6
Varity_R		0.11
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-19042849;