19-18931578-A-G

Variant names:

• chr19-18931578-A-G
• rs57792670
• NM_004838.4:c.738T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004838.4(HOMER3):​c.738T>C​(p.Gly246Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,612,976 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (172 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (173 hom.)
• Consequence: HOMER3 NM_004838.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.01
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-18931578-A-G is Benign according to our data. Variant chr19-18931578-A-G is described in ClinVar as Benign. ClinVar VariationId is 781464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0847 is higher than 0.05.

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.738T>C	p.Gly246Gly	synonymous	Exon 8 of 10	NP_004829.3
	HOMER3	NM_001145722.2		c.738T>C	p.Gly246Gly	synonymous	Exon 8 of 10	NP_001139194.1	Q9NSC5-1
	HOMER3	NM_001145721.1		c.738T>C	p.Gly246Gly	synonymous	Exon 8 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.738T>C	p.Gly246Gly	synonymous	Exon 8 of 10	ENSP00000376162.2	Q9NSC5-1
	HOMER3	ENST00000539827.5	TSL:1	c.738T>C	p.Gly246Gly	synonymous	Exon 7 of 9	ENSP00000439937.1	Q9NSC5-1
	HOMER3	ENST00000542541.6	TSL:1	c.738T>C	p.Gly246Gly	synonymous	Exon 8 of 10	ENSP00000446026.1	Q9NSC5-1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3848 AN: 152028 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00657 AC: 1645 AN: 250268 AF XY: 0.00483

Gnomad AFR exome AF: 0.0879

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00272 AC: 3980 AN: 1460830 Hom.: 173 Cov.: 32 AF XY: 0.00236 AC XY: 1714 AN XY: 726708

African (AFR) AF: 0.0920 AC: 3079 AN: 33474

American (AMR) AF: 0.00474 AC: 212 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00436 AC: 114 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52600

Middle Eastern (MID) AF: 0.00490 AC: 28 AN: 5716

European-Non Finnish (NFE) AF: 0.000123 AC: 137 AN: 1111912

Other (OTH) AF: 0.00653 AC: 394 AN: 60366

GnomAD4 genome AF: 0.0254 AC: 3871 AN: 152146 Hom.: 172 Cov.: 32 AF XY: 0.0245 AC XY: 1819 AN XY: 74382

African (AFR) AF: 0.0871 AC: 3615 AN: 41502

American (AMR) AF: 0.0114 AC: 174 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67996

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0120 Hom.: 35

Bravo AF: 0.0294

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.66
PhyloP100		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs57792670; hg19: chr19-19042387;