17-7218592-C-A

Variant names:

• chr17-7218592-C-A
• rs1014318240
• ENST00000648172.9:c.67G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000648172.9(DLG4):​c.67G>T​(p.Ala23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DLG4 ENST00000648172.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17183879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001365.5	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 22		NP_001356.1
DLG4	NM_001321074.1	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 22		NP_001308003.1
DLG4	NR_135527.1	n.1268G>T		non_coding_transcript_exon_variant	Exon 2 of 21
ACADVL	NM_001270447.2	c.131+774C>A		intron_variant	Intron 2 of 20		NP_001257376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000648172.9	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 22			ENSP00000497806.3
DLG4	ENST00000399510.8	c.67G>T	p.Ala23Ser	missense_variant	Exon 2 of 22	1		ENSP00000382428.3
DLG4	ENST00000491753.2	n.67G>T		non_coding_transcript_exon_variant	Exon 2 of 21	2		ENSP00000467897.2
ACADVL	ENST00000543245.6	c.131+774C>A		intron_variant	Intron 2 of 20	2		ENSP00000438689.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1414020 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698770

African (AFR) AF: 0.00 AC: 0 AN: 32318

American (AMR) AF: 0.00 AC: 0 AN: 37284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25300

East Asian (EAS) AF: 0.00 AC: 0 AN: 37046

South Asian (SAS) AF: 0.00 AC: 0 AN: 80182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087340

Other (OTH) AF: 0.00 AC: 0 AN: 58678

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 05, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T
Eigen	Benign	0.0074
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PROVEAN	Benign	0.35	.;N
REVEL	Benign	0.038
Sift	Benign	0.071	.;T
Sift4G	Benign	0.71	.;T
Polyphen		0.76	P;B
Vest4		0.48
MutPred		0.45		Gain of phosphorylation at A23 (P = 0.0587);Gain of phosphorylation at A23 (P = 0.0587);
MVP		0.59
MPC		1.1
ClinPred		0.63	D
GERP RS		4.6
gMVP		0.24

Splicing

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

Other links and lift over

dbSNP: rs1014318240; hg19: chr17-7121911;