Genetic Variant DLG4:c.159+455G>T (chr17-7217786-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_001270447.2(ACADVL):c.99C>A(p.Gly33Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,535,062 control chromosomes in the GnomAD database, including 927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.024 ( 68 hom., cov: 30)

Exomes 𝑓: 0.032 ( 859 hom. )

Consequence

ACADVL
NM_001270447.2 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.382

Publications

1 publications found

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]

DLG4 links:

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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 17-7217786-C-A is Benign according to our data. Variant chr17-7217786-C-A is described in ClinVar as Benign. ClinVar VariationId is 2428699.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.382 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3626/152048) while in subpopulation NFE AF = 0.0361 (2450/67958). AF 95% confidence interval is 0.0349. There are 68 homozygotes in GnomAd4. There are 1714 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 68 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270447.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLG4	NM_001365.5	MANE Plus Clinical	c.159+455G>T		intron	N/A	NP_001356.1	P78352-2
ACADVL	NM_001270447.2		c.99C>A	p.Gly33Gly	synonymous	Exon 2 of 21	NP_001257376.1	P49748-3
DLG4	NM_001321074.1		c.159+455G>T		intron	N/A	NP_001308003.1	B9EGL1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DLG4	ENST00000648172.9	MANE Plus Clinical	c.159+455G>T	intron	N/A	ENSP00000497806.3	P78352-2
DLG4	ENST00000399510.8	TSL:1	c.159+455G>T	intron	N/A	ENSP00000382428.3	B9EGL1
DLG4	ENST00000491753.2	TSL:2	n.159+455G>T	intron	N/A	ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3614

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00738

Gnomad AMI

AF:

0.0791

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0219

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0360

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0239

AC:

3067

AN:

128336

AF XY:

0.0250

show subpopulations

Gnomad AFR exome

AF:

0.00641

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.000288

Gnomad FIN exome

AF:

0.0202

Gnomad NFE exome

AF:

0.0360

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0319

AC:

44163

AN:

1383014

Hom.:

859

Cov.:

AF XY:

0.0318

AC XY:

21686

AN XY:

682426

show subpopulations

African (AFR)

AF:

0.00630

AC:

199

AN:

31592

American (AMR)

AF:

0.0179

AC:

637

AN:

35676

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

476

AN:

25158

East Asian (EAS)

AF:

0.000168

AC:

AN:

35730

South Asian (SAS)

AF:

0.0245

AC:

1939

AN:

79224

European-Finnish (FIN)

AF:

0.0234

AC:

783

AN:

33462

Middle Eastern (MID)

AF:

0.0408

AC:

232

AN:

5692

European-Non Finnish (NFE)

AF:

0.0353

AC:

38126

AN:

1078602

Other (OTH)

AF:

0.0305

AC:

1765

AN:

57878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

2195

4390

6585

8780

10975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1410

2820

4230

5640

7050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0238

AC:

3626

AN:

152048

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1714

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00770

AC:

319

AN:

41450

American (AMR)

AF:

0.0204

AC:

312

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0219

AC:

105

AN:

4800

European-Finnish (FIN)

AF:

0.0225

AC:

238

AN:

10594

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0361

AC:

2450

AN:

67958

Other (OTH)

AF:

0.0284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

185

370

556

741

926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0302

Hom.:

Bravo

AF:

0.0227

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

-0.38

PromoterAI

-0.15

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over