17-7217739-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000399510.8(DLG4):c.159+502T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,534,904 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: DLG4 ENST00000399510.8 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.287

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=0.005048126).
• BS2: High AC in GnomAd at 101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_001270447.2	c.52A>G	p.Ile18Val	missense_variant	2/21
DLG4	NM_001321074.1	c.159+502T>C		intron_variant
DLG4	NM_001365.4	c.159+502T>C		intron_variant
DLG4	NR_135527.1	n.1360+502T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLG4	ENST00000399510.8	c.159+502T>C		intron_variant		1
ACADVL	ENST00000543245.6	c.52A>G	p.Ile18Val	missense_variant	2/21	2
DLG4	ENST00000648172.8	c.159+502T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000665 AC: 101 AN: 151888 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00747

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000320 AC: 41 AN: 128324 Hom.: 0 AF XY: 0.000299 AC XY: 21 AN XY: 70286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00519

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000251 AC: 347 AN: 1383016 Hom.: 1 Cov.: 31 AF XY: 0.000262 AC XY: 179 AN XY: 682436

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: 0.00

Gnomad4 FIN exome AF: 0.00562

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome AF: 0.000665 AC: 101 AN: 151888 Hom.: 0 Cov.: 30 AF XY: 0.000957 AC XY: 71 AN XY: 74190

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00747

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

ACADVL: PP3 -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 19, 2014

- -

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.5
Dann	Benign	0.81
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.0050	T
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.28
Sift	Benign	0.13	T
Vest4		0.13
MutPred		0.082		Gain of ubiquitination at K16 (P = 0.0918);
MVP		0.37
MPC		0.16
ClinPred		0.12	T
GERP RS		-3.7
gMVP		0.19

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs730880036; hg19: chr17-7121058; COSMIC: COSV100263795; COSMIC: COSV100263795;