18-3499301-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_004746.4(DLGAP1):​c.2818G>A​(p.Glu940Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,431,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

DLGAP1
NM_004746.4 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.39694232).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DLGAP1NM_004746.4 linkc.2818G>A p.Glu940Lys missense_variant Exon 13 of 13 ENST00000315677.8 NP_004737.2 O14490-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DLGAP1ENST00000315677.8 linkc.2818G>A p.Glu940Lys missense_variant Exon 13 of 13 5 NM_004746.4 ENSP00000316377.3 O14490-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000279
AC:
4
AN:
1431126
Hom.:
0
Cov.:
31
AF XY:
0.00000282
AC XY:
2
AN XY:
709254
show subpopulations
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:
0.00000364
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 02, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2818G>A (p.E940K) alteration is located in exon 13 (coding exon 10) of the DLGAP1 gene. This alteration results from a G to A substitution at nucleotide position 2818, causing the glutamic acid (E) at amino acid position 940 to be replaced by a lysine (K). 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
Pathogenic
0.78
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
.;.;.;.;T;T;.;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;.;D;D;D;D;D;D
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.40
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Pathogenic
3.1
.;.;.;.;.;M;.;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-3.2
D;D;D;D;.;D;D;D;.
REVEL
Uncertain
0.44
Sift
Uncertain
0.0010
D;D;D;D;.;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;D;.;.;.
Vest4
0.46
MutPred
0.60
.;.;.;.;.;Gain of ubiquitination at E940 (P = 0.0428);.;.;.;
MVP
0.70
MPC
1.9
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.88
gMVP
0.80

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: chr18-3499299; API