chr17-7218550-C-T

Variant names:

• chr17-7218550-C-T
• rs372479041
• NM_001365.5:c.109G>A

Variant summary

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

The NM_001365.5(DLG4):​c.109G>A​(p.Ala37Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DLG4 NM_001365.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 1 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: ClinGen, G2P, Orphanet, 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=0.21902657).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	NM_001365.5	MANE Plus Clinical	c.109G>A	p.Ala37Thr	missense	Exon 2 of 22	NP_001356.1	P78352-2
	DLG4	NM_001321074.1		c.109G>A	p.Ala37Thr	missense	Exon 2 of 22	NP_001308003.1	B9EGL1
	ACADVL	NM_001270447.2		c.131+732C>T		intron	N/A	NP_001257376.1	P49748-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	ENST00000648172.9	MANE Plus Clinical	c.109G>A	p.Ala37Thr	missense	Exon 2 of 22	ENSP00000497806.3	P78352-2
	DLG4	ENST00000399510.8	TSL:1	c.109G>A	p.Ala37Thr	missense	Exon 2 of 22	ENSP00000382428.3	B9EGL1
	DLG4	ENST00000491753.2	TSL:2	n.109G>A		non_coding_transcript_exon	Exon 2 of 21	ENSP00000467897.2	B7Z3U2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 167756 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408266 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695424

African (AFR) AF: 0.00 AC: 0 AN: 31962

American (AMR) AF: 0.00 AC: 0 AN: 36616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.00 AC: 0 AN: 36456

South Asian (SAS) AF: 0.00 AC: 0 AN: 79758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084286

Other (OTH) AF: 0.00 AC: 0 AN: 58438

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00000858 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.0
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.095
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.88	P
Vest4		0.58
MVP		0.56
MPC		1.1
ClinPred		0.94	D
GERP RS		4.4
gMVP		0.52

Splicing

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

Other links and lift over

dbSNP: rs372479041; hg19: chr17-7121869;