18-3502620-G-T

Variant summary

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

The NM_004746.4(DLGAP1):c.2597C>A(p.Thr866Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DLGAP1 NM_004746.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

Genes affected

DLGAP1 (HGNC:2905): (DLG associated protein 1) Predicted to enable molecular adaptor activity. Predicted to be a structural constituent of postsynaptic density. Predicted to be involved in several processes, including aggresome assembly; regulation of postsynaptic neurotransmitter receptor activity; and regulation of proteasomal protein catabolic process. Predicted to be located in plasma membrane. Predicted to be part of postsynaptic density. Predicted to be active in glutamatergic synapse and postsynaptic density, intracellular component. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLGAP1	NM_004746.4	c.2597C>A	p.Thr866Asn	missense_variant	12/13	ENST00000315677.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLGAP1	ENST00000315677.8	c.2597C>A	p.Thr866Asn	missense_variant	12/13	5	NM_004746.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 21, 2023

The c.2597C>A (p.T866N) alteration is located in exon 12 (coding exon 9) of the DLGAP1 gene. This alteration results from a C to A substitution at nucleotide position 2597, causing the threonine (T) at amino acid position 866 to be replaced by an asparagine (N). 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	0.13
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D;D;D;.;D;D;D;.;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D;D;.;D;D;D;.;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.90	P;.;.;.;.;P;.;.;.;P;.
Vest4		0.53
MutPred		0.76		.;.;.;.;.;Loss of phosphorylation at T866 (P = 0.0176);.;.;.;.;Loss of phosphorylation at T866 (P = 0.0176);
MVP		0.52
MPC		1.4
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.55

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: chr18-3502618;