17-7218565-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The ENST00000399510.8(DLG4):ā€‹c.94A>Gā€‹(p.Ser32Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000253 in 1,564,080 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 Benign (ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 32)
Exomes š‘“: 0.00027 ( 0 hom. )

Consequence

DLG4
ENST00000399510.8 missense

Scores

2
14

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.10
Variant links:
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]
ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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 4.6509 (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=0.007270336).
BP6
Variant 17-7218565-T-C is Benign according to our data. Variant chr17-7218565-T-C is described in ClinVar as [Benign]. Clinvar id is 2647321.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DLG4NM_001365.4 linkuse as main transcriptc.94A>G p.Ser32Gly missense_variant 2/22
DLG4NM_001321074.1 linkuse as main transcriptc.94A>G p.Ser32Gly missense_variant 2/22
ACADVLNM_001270447.2 linkuse as main transcriptc.131+747T>C intron_variant
DLG4NR_135527.1 linkuse as main transcriptn.1295A>G non_coding_transcript_exon_variant 2/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DLG4ENST00000399510.8 linkuse as main transcriptc.94A>G p.Ser32Gly missense_variant 2/221
DLG4ENST00000648172.8 linkuse as main transcriptc.94A>G p.Ser32Gly missense_variant 2/22 P78352-2
ACADVLENST00000543245.6 linkuse as main transcriptc.131+747T>C intron_variant 2 P49748-3
DLG4ENST00000491753.2 linkuse as main transcriptc.94A>G p.Ser32Gly missense_variant, NMD_transcript_variant 2/212

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00352
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000649
AC:
112
AN:
172638
Hom.:
0
AF XY:
0.000846
AC XY:
78
AN XY:
92194
show subpopulations
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:
0.00463
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000280
Gnomad OTH exome
AF:
0.000213
GnomAD4 exome
AF:
0.000268
AC:
378
AN:
1411842
Hom.:
0
Cov.:
31
AF XY:
0.000371
AC XY:
259
AN XY:
697582
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:
0.00411
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000249
Gnomad4 OTH exome
AF:
0.000359
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00352
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000166
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.000382
AC:
45
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

DLG4-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 17, 2021This 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). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024DLG4: PP2, BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
.;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.0022
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.68
T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.0073
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
D;N;N
PROVEAN
Benign
-0.65
.;N
REVEL
Benign
0.048
Sift
Uncertain
0.0090
.;D
Sift4G
Benign
0.088
.;T
Polyphen
0.22
B;B
Vest4
0.53
MutPred
0.60
Gain of catalytic residue at S32 (P = 0.0244);Gain of catalytic residue at S32 (P = 0.0244);
MVP
0.62
MPC
1.1
ClinPred
0.046
T
GERP RS
4.5
gMVP
0.37

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs565495109; hg19: chr17-7121884; API