chr17-7225408-C-T

Variant names:

• chr17-7225408-C-T
• rs1054280
• NM_004422.3:c.*457G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004422.3(DVL2):​c.*457G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 467,190 control chromosomes in the GnomAD database, including 541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (159 hom., cov: 32)
  • Exomes 𝑓: 0.024 (382 hom.)
• Consequence: DVL2 NM_004422.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.37
• Publications: 5 publications found

Genes affected

DVL2 (HGNC:3086): (dishevelled segment polarity protein 2) This gene encodes a member of the dishevelled (dsh) protein family. The vertebrate dsh proteins have approximately 40% amino acid sequence similarity with Drosophila dsh. This gene encodes a 90-kD protein that undergoes posttranslational phosphorylation to form a 95-kD cytoplasmic protein, which may play a role in the signal transduction pathway mediated by multiple Wnt proteins. The mechanisms of dishevelled function in Wnt signaling are likely to be conserved among metazoans. [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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-7225408-C-T is Benign according to our data. Variant chr17-7225408-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1195261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004422.3. 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
	DVL2	NM_004422.3	MANE Select	c.*457G>A		3_prime_UTR	Exon 15 of 15	NP_004413.1	O14641
	ACADVL	NM_000018.4	MANE Select	c.*311C>T		downstream_gene	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.*311C>T		downstream_gene	N/A	NP_001257376.1	P49748-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DVL2	ENST00000005340.10	TSL:1 MANE Select	c.*457G>A		3_prime_UTR	Exon 15 of 15	ENSP00000005340.4	O14641
	DVL2	ENST00000951245.1		c.*457G>A		3_prime_UTR	Exon 15 of 15	ENSP00000621304.1
	DVL2	ENST00000930220.1		c.*457G>A		3_prime_UTR	Exon 15 of 15	ENSP00000600279.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4688 AN: 152070 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.0241 AC: 7600 AN: 315002 Hom.: 382 Cov.: 3 AF XY: 0.0235 AC XY: 3937 AN XY: 167450

African (AFR) AF: 0.0438 AC: 410 AN: 9368

American (AMR) AF: 0.0544 AC: 719 AN: 13222

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 355 AN: 9394

East Asian (EAS) AF: 0.185 AC: 3307 AN: 17902

South Asian (SAS) AF: 0.0201 AC: 834 AN: 41484

European-Finnish (FIN) AF: 0.0203 AC: 326 AN: 16036

Middle Eastern (MID) AF: 0.0277 AC: 37 AN: 1336

European-Non Finnish (NFE) AF: 0.00588 AC: 1109 AN: 188686

Other (OTH) AF: 0.0286 AC: 503 AN: 17574

GnomAD4 genome AF: 0.0309 AC: 4706 AN: 152188 Hom.: 159 Cov.: 32 AF XY: 0.0338 AC XY: 2517 AN XY: 74384

African (AFR) AF: 0.0457 AC: 1896 AN: 41532

American (AMR) AF: 0.0587 AC: 898 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3470

East Asian (EAS) AF: 0.168 AC: 862 AN: 5142

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4826

European-Finnish (FIN) AF: 0.0261 AC: 276 AN: 10582

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00623 AC: 424 AN: 68028

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0218 Hom.: 10

Bravo AF: 0.0352

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1054280; hg19: chr17-7128727;