chr17-7190731-C-T

Position:

• chr17-7190731-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001321075.3(DLG4):​c.2152G>A​(p.Val718Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,744 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: DLG4 NM_001321075.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.45

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]

DLG4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01369518).
• BP6: Variant 17-7190731-C-T is Benign according to our data. Variant chr17-7190731-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 774928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 262 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.2152G>A	p.Val718Ile	missense_variant	20/20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.2152G>A	p.Val718Ile	missense_variant	20/20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000648172.8	c.2281G>A	p.Val761Ile	missense_variant	22/22			ENSP00000497806.3
DLG4	ENST00000648896.1	c.2251G>A	p.Val751Ile	missense_variant	20/20			ENSP00000497546.1
DLG4	ENST00000649520.1	c.1972G>A	p.Val658Ile	missense_variant	19/19			ENSP00000497647.1
DLG4	ENST00000491753.2	n.*167G>A		non_coding_transcript_exon_variant	21/21	2		ENSP00000467897.2
DLG4	ENST00000491753.2	n.*167G>A		3_prime_UTR_variant	21/21	2		ENSP00000467897.2

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00177 AC: 442 AN: 249144 Hom.: 3 AF XY: 0.00182 AC XY: 246 AN XY: 135174

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00242 AC: 3543 AN: 1461504 Hom.: 7 Cov.: 31 AF XY: 0.00234 AC XY: 1701 AN XY: 727036

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.00145 AC XY: 108 AN XY: 74442

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00253 Hom.: 2

Bravo AF: 0.00196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00203 AC: 17

ExAC AF: 0.00174 AC: 211

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00379

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	DLG4: PP2, BP4, BS1 -

DLG4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.42	.;.;T;T;T;.;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D;D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	.;.;N;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.35	.;N;N;.;.;.;.;.
REVEL	Benign	0.048
Sift	Benign	0.26	.;T;T;.;.;.;.;.
Sift4G	Benign	0.36	.;T;T;.;.;.;.;.
Polyphen		0.0010	B;.;B;.;B;.;.;.
Vest4		0.13, 0.13
MVP		0.48
MPC		1.1
ClinPred		0.012	T
GERP RS		4.1
Varity_R		0.086
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147232488; hg19: chr17-7094050;