17-7191908-G-A

Position:

• chr17-7191908-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

The NM_001321075.3(DLG4):​c.1961C>T​(p.Ser654Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 1,333,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: DLG4 NM_001321075.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56

Genes affected

DLG4 (HGNC:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DLG4. . Gene score misZ 4.933 (greater than the threshold 3.09). Trascript score misZ 4.8337 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder 62.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.1961C>T	p.Ser654Phe	missense_variant	18/20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.1961C>T	p.Ser654Phe	missense_variant	18/20	2	NM_001321075.3	ENSP00000382425	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000621 AC: 1 AN: 161148 Hom.: 0 AF XY: 0.0000114 AC XY: 1 AN XY: 87410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000900 AC: 12 AN: 1333138 Hom.: 0 Cov.: 31 AF XY: 0.0000107 AC XY: 7 AN XY: 654518

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: 0.0000115

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000832 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DLG4-related synaptopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 19, 2021

The DLG4 c.2090C>T (p.Ser697Phe) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is reported at a frequency of 0.000013 in the European (non-Finnish) population of the Genome Aggregation Database. However, this frequency is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. The p.Ser697Phe variant is located at a conserved residue in the guanylate kinase-like domain of the PSD-95 protein. In silico tools consistently predict a functional effect of this variant, but these predictions have not been tested experimentally. Based on the available evidence, the p.Ser697Phe variant is classified as a variant of uncertain significance for DLG4-related synaptopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;D;T;T;.;T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Pathogenic	4.2	.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.2	.;D;D;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;D;D;.;.;.;.;.
Polyphen		0.20	B;.;B;.;B;.;.;.
Vest4		0.80, 0.80
MutPred		0.81		.;.;Loss of phosphorylation at S654 (P = 0.0517);.;.;.;.;.;
MVP		0.85
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.98

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: rs752934560; hg19: chr17-7095227;