rs72839706

Variant names:

• chr17-7217786-C-A
• rs72839706
• ENST00000648172.9:c.159+455G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000491753.2(DLG4):​n.159+455G>T variant causes a intron 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: DLG4 ENST00000491753.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.382
• 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: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 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 id is 2428699.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 AC in GnomAd4 at 3626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLG4	NM_001321075.3	c.-639G>T		upstream_gene_variant		ENST00000399506.9	NP_001308004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLG4	ENST00000648172.9	c.159+455G>T		intron_variant	Intron 3 of 21			ENSP00000497806.3
DLG4	ENST00000491753.2	n.159+455G>T		intron_variant	Intron 3 of 20	2		ENSP00000467897.2
DLG4	ENST00000399506.9	c.-639G>T		upstream_gene_variant		2	NM_001321075.3	ENSP00000382425.2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3614 AN: 151932 Hom.: 67 Cov.: 30

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

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.: 31 AF XY: 0.0318 AC XY: 21686 AN XY: 682426

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: 6 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

GnomAD4 genome AF: 0.0238 AC: 3626 AN: 152048 Hom.: 68 Cov.: 30 AF XY: 0.0231 AC XY: 1714 AN XY: 74314

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: 58 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 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: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0361 AC: 2450 AN: 67958

Other (OTH) AF: 0.0284 AC: 60 AN: 2112

Alfa AF: 0.0302 Hom.: 19

Bravo AF: 0.0227

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Benign:1

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		-0.38
PromoterAI		-0.15	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs72839706; hg19: chr17-7121105;