17-7217159-T-C

Variant names:

• chr17-7217159-T-C
• rs763975299
• NM_001321075.3:c.-12A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

ACADVL Gene-Disease associations (from GenCC):

• very long chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.-12A>G		5_prime_UTR_variant	Exon 1 of 20	ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000399506.9	c.-12A>G		5_prime_UTR_variant	Exon 1 of 20	2	NM_001321075.3	ENSP00000382425.2
DLG4	ENST00000647975.1	c.-12A>G		5_prime_UTR_variant	Exon 1 of 7			ENSP00000497912.1
DLG4	ENST00000648172.9	c.159+1082A>G		intron_variant	Intron 3 of 21			ENSP00000497806.3
DLG4	ENST00000491753.2	n.159+1082A>G		intron_variant	Intron 3 of 20	2		ENSP00000467897.2

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

GnomAD2 exomes AF: 0.00129 AC: 34 AN: 26390 AF XY: 0.00114

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 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

African (AFR) AF: 0.000128 AC: 3 AN: 23384

American (AMR) AF: 0.000106 AC: 1 AN: 9392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15070

East Asian (EAS) AF: 0.00 AC: 0 AN: 27150

South Asian (SAS) AF: 0.000359 AC: 10 AN: 27830

European-Finnish (FIN) AF: 0.00147 AC: 56 AN: 38156

Middle Eastern (MID) AF: 0.000531 AC: 2 AN: 3764

European-Non Finnish (NFE) AF: 0.000686 AC: 649 AN: 946434

Other (OTH) AF: 0.000505 AC: 23 AN: 45548

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41406

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5052

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4800

European-Finnish (FIN) AF: 0.00218 AC: 23 AN: 10562

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000781 AC: 53 AN: 67896

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

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

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		4.8
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
PromoterAI		0.0090	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.69
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

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