17-7217159-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001321075.3(DLG4):c.-12A>G variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.000652 in 1,288,510 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: DLG4 NM_001321075.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.76

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21365088).
• BP6: Variant 17-7217159-T-C is Benign according to our data. Variant chr17-7217159-T-C is described in ClinVar as [Benign]. Clinvar id is 1176656.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLG4	NM_001321075.3	c.-12A>G		5_prime_UTR_variant	1/20	ENST00000399506.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG4	ENST00000399506.9	c.-12A>G		5_prime_UTR_variant	1/20	2	NM_001321075.3	A1

Frequencies

GnomAD3 genomes AF: 0.000633 AC: 96 AN: 151668 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.00218

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000781

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00129 AC: 34 AN: 26390 Hom.: 0 AF XY: 0.00114 AC XY: 14 AN XY: 12258

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: 0.00215

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.000655 AC: 744 AN: 1136728 Hom.: 1 Cov.: 32 AF XY: 0.000609 AC XY: 332 AN XY: 544790

Gnomad4 AFR exome AF: 0.000128

Gnomad4 AMR exome AF: 0.000106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00147

Gnomad4 NFE exome AF: 0.000686

Gnomad4 OTH exome AF: 0.000505

GnomAD4 genome AF: 0.000632 AC: 96 AN: 151782 Hom.: 0 Cov.: 29 AF XY: 0.000687 AC XY: 51 AN XY: 74190

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00218

Gnomad4 NFE AF: 0.000781

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000487

ExAC AF: 0.000340 AC: 8

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

DLG4: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Benign	0.90
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.21	T
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	0.91	D;D;D;D;D;D
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Vest4		0.58
MVP		0.91
MPC		0.89
ClinPred		0.18	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.69

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: rs763975299; hg19: chr17-7120478; COSMIC: COSV57238298; COSMIC: COSV57238298;