17-7219921-T-TGGGCGTGCAGGACGC

Variant names:

• chr17-7219921-T-TGGGCGTGCAGGACGC
• rs6145976
• ENST00000350303.9:c.-63_-49dupGGGCGTGCAGGACGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000322910.9(ACADVL):​n.-63_-49dupGGGCGTGCAGGACGC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,554,922 control chromosomes in the GnomAD database, including 250,780 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20943 hom., cov: 0)
  • Exomes 𝑓: 0.57 (229837 hom.)
• Consequence: ACADVL ENST00000322910.9 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.14
• Publications: 6 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder 62

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-7219921-T-TGGGCGTGCAGGACGC is Benign according to our data. Variant chr17-7219921-T-TGGGCGTGCAGGACGC is described in ClinVar as Benign. ClinVar VariationId is 166637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000322910.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLG4	NR_135527.1		n.115_129dupGCGTCCTGCACGCCC		non_coding_transcript_exon	Exon 1 of 21
	DLG4	NM_001321074.1		c.-1087_-1073dupGCGTCCTGCACGCCC		5_prime_UTR	Exon 1 of 22	NP_001308003.1
	ACADVL	NM_001270447.2		c.132-200_132-186dupGGGCGTGCAGGACGC		intron	N/A	NP_001257376.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000350303.9	TSL:1	c.-63_-49dupGGGCGTGCAGGACGC		5_prime_UTR	Exon 1 of 19	ENSP00000344152.5
	ACADVL	ENST00000322910.9	TSL:2	n.-63_-49dupGGGCGTGCAGGACGC		non_coding_transcript_exon	Exon 1 of 19	ENSP00000325395.5
	ACADVL	ENST00000577191.5	TSL:2	n.15_29dupGGGCGTGCAGGACGC		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77778 AN: 151612 Hom.: 20921 Cov.: 0

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.569 AC: 798723 AN: 1403190 Hom.: 229837 Cov.: 99 AF XY: 0.572 AC XY: 396860 AN XY: 693630

African (AFR) AF: 0.330 AC: 10890 AN: 33008

American (AMR) AF: 0.476 AC: 17314 AN: 36368

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14372 AN: 25240

East Asian (EAS) AF: 0.453 AC: 17220 AN: 37994

South Asian (SAS) AF: 0.605 AC: 48538 AN: 80294

European-Finnish (FIN) AF: 0.611 AC: 23390 AN: 38264

Middle Eastern (MID) AF: 0.625 AC: 3561 AN: 5696

European-Non Finnish (NFE) AF: 0.580 AC: 631135 AN: 1087706

Other (OTH) AF: 0.551 AC: 32303 AN: 58620

GnomAD4 genome AF: 0.513 AC: 77841 AN: 151732 Hom.: 20943 Cov.: 0 AF XY: 0.518 AC XY: 38438 AN XY: 74168

African (AFR) AF: 0.338 AC: 14004 AN: 41458

American (AMR) AF: 0.522 AC: 7954 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1935 AN: 3460

East Asian (EAS) AF: 0.481 AC: 2464 AN: 5120

South Asian (SAS) AF: 0.597 AC: 2867 AN: 4802

European-Finnish (FIN) AF: 0.648 AC: 6853 AN: 10570

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 39912 AN: 67772

Other (OTH) AF: 0.551 AC: 1158 AN: 2100

Alfa AF: 0.484 Hom.: 2208

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Very long chain acyl-CoA dehydrogenase deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6145976; hg19: chr17-7123240; COSMIC: COSV57236401; COSMIC: COSV57236401;