18-3581933-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004746.4(DLGAP1):c.1907C>T(p.Thr636Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: DLGAP1 NM_004746.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11639494).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLGAP1	NM_004746.4	c.1907C>T	p.Thr636Met	missense_variant	8/13	ENST00000315677.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLGAP1	ENST00000315677.8	c.1907C>T	p.Thr636Met	missense_variant	8/13	5	NM_004746.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152154 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: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 249566 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000602 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

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 15, 2022

The c.1907C>T (p.T636M) alteration is located in exon 8 (coding exon 5) of the DLGAP1 gene. This alteration results from a C to T substitution at nucleotide position 1907, causing the threonine (T) at amino acid position 636 to be replaced by a methionine (M). 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	0.078
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	24
Dann	Benign	0.96
Eigen	Benign	-0.033
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;N;.;N;N;N;.;N;.
REVEL	Benign	0.061
Sift	Uncertain	0.022	D;D;D;D;.;D;D;D;.;D;.
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.29	B;.;.;.;.;P;.;.;.;P;.
Vest4		0.083
MutPred		0.24		.;.;.;.;.;Loss of glycosylation at T636 (P = 0.0203);.;.;.;.;Loss of glycosylation at T636 (P = 0.0203);
MVP		0.34
MPC		0.99
ClinPred		0.092	T
GERP RS		5.4
Varity_R		0.026
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs755948170; hg19: chr18-3581931; COSMIC: COSV59787126; COSMIC: COSV59787126;