17-7218565-T-C

Variant summary

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

The ENST00000399510.8(DLG4):c.94A>G(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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: DLG4 ENST00000399510.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.10

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DLG4
• 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 [Likely_benign]. Clinvar id is 2647321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG4	NM_001365.4	c.94A>G	p.Ser32Gly	missense_variant	2/22
DLG4	NM_001321074.1	c.94A>G	p.Ser32Gly	missense_variant	2/22
ACADVL	NM_001270447.2	c.131+747T>C		intron_variant
DLG4	NR_135527.1	n.1295A>G		non_coding_transcript_exon_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG4	ENST00000399510.8	c.94A>G	p.Ser32Gly	missense_variant	2/22	1
DLG4	ENST00000648172.8	c.94A>G	p.Ser32Gly	missense_variant	2/22
ACADVL	ENST00000543245.6	c.131+747T>C		intron_variant		2
DLG4	ENST00000491753.2	c.94A>G	p.Ser32Gly	missense_variant, NMD_transcript_variant	2/21	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152120 Hom.: 0 Cov.: 32

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

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

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

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/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DLG4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

DLG4: 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
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
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

Other links and lift over

dbSNP: rs565495109; hg19: chr17-7121884;