chr19-18929544-G-A

Variant names:

• chr19-18929544-G-A
• rs376331681
• NM_004838.4:c.985C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004838.4(HOMER3):​c.985C>T​(p.Arg329Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 1,557,540 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: HOMER3 NM_004838.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.266541).

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.985C>T	p.Arg329Trp	missense	Exon 10 of 10	NP_004829.3
	HOMER3	NM_001145722.2		c.985C>T	p.Arg329Trp	missense	Exon 10 of 10	NP_001139194.1	Q9NSC5-1
	HOMER3	NM_001145721.1		c.976C>T	p.Arg326Trp	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.985C>T	p.Arg329Trp	missense	Exon 10 of 10	ENSP00000376162.2	Q9NSC5-1
	HOMER3	ENST00000539827.5	TSL:1	c.985C>T	p.Arg329Trp	missense	Exon 9 of 9	ENSP00000439937.1	Q9NSC5-1
	HOMER3	ENST00000542541.6	TSL:1	c.985C>T	p.Arg329Trp	missense	Exon 10 of 10	ENSP00000446026.1	Q9NSC5-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000656 AC: 1 AN: 152408 AF XY: 0.0000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1405192 Hom.: 0 Cov.: 44 AF XY: 0.00000576 AC XY: 4 AN XY: 694650

African (AFR) AF: 0.00 AC: 0 AN: 32136

American (AMR) AF: 0.0000267 AC: 1 AN: 37416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 36696

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4994

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1085110

Other (OTH) AF: 0.00 AC: 0 AN: 58270

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152348 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74498

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

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.077
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.36
MPC		1.4
ClinPred		0.98	D
GERP RS		0.25
Varity_R		0.43
gMVP		0.44
Mutation Taster		=79/21	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: rs376331681; hg19: chr19-19040353;