17-7218634-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001365.5(DLG4):​c.25A>G​(p.Arg9Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DLG4
NM_001365.5 missense

Scores

1
2
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0420
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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 4.6539 (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=0.10298464).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DLG4NM_001365.5 linkuse as main transcriptc.25A>G p.Arg9Gly missense_variant 2/22 NP_001356.1 P78352-2B7Z647B9EGL1
DLG4NM_001321074.1 linkuse as main transcriptc.25A>G p.Arg9Gly missense_variant 2/22 NP_001308003.1 B9EGL1
ACADVLNM_001270447.2 linkuse as main transcriptc.131+816T>C intron_variant NP_001257376.1 P49748-3
DLG4NR_135527.1 linkuse as main transcriptn.1226A>G non_coding_transcript_exon_variant 2/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DLG4ENST00000648172.8 linkuse as main transcriptc.25A>G p.Arg9Gly missense_variant 2/22 ENSP00000497806.3 P78352-2
DLG4ENST00000399510.8 linkuse as main transcriptc.25A>G p.Arg9Gly missense_variant 2/221 ENSP00000382428.3 B9EGL1
DLG4ENST00000491753.2 linkuse as main transcriptn.25A>G non_coding_transcript_exon_variant 2/212 ENSP00000467897.2 B7Z3U2
ACADVLENST00000543245.6 linkuse as main transcriptc.131+816T>C intron_variant 2 ENSP00000438689.2 P49748-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 04, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
.;T
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.43
N
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-1.0
T
PROVEAN
Benign
-0.24
.;N
REVEL
Benign
0.048
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.043
.;D
Polyphen
0.60
P;B
Vest4
0.67
MutPred
0.30
Loss of MoRF binding (P = 0.0043);Loss of MoRF binding (P = 0.0043);
MVP
0.48
MPC
1.4
ClinPred
0.64
D
GERP RS
-0.14
gMVP
0.47

Splicing

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: chr17-7121953; API