8-26583890-A-G

Variant names:

• chr8-26583890-A-G
• NM_001197293.3:c.535A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001197293.3(DPYSL2):​c.535A>G​(p.Thr179Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPYSL2 NM_001197293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

DPYSL2 (HGNC:3014): (dihydropyrimidinase like 2) This gene encodes a member of the collapsin response mediator protein family. Collapsin response mediator proteins form homo- and hetero-tetramers and facilitate neuron guidance, growth and polarity. The encoded protein promotes microtubule assembly and is required for Sema3A-mediated growth cone collapse, and also plays a role in synaptic signaling through interactions with calcium channels. This gene has been implicated in multiple neurological disorders, and hyperphosphorylation of the encoded protein may play a key role in the development of Alzheimer's disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.535A>G	p.Thr179Ala	missense_variant	Exon 3 of 14	ENST00000521913.7	NP_001184222.1
DPYSL2	NM_001386.6	c.220A>G	p.Thr74Ala	missense_variant	Exon 3 of 14		NP_001377.1
DPYSL2	NM_001244604.2	c.112A>G	p.Thr38Ala	missense_variant	Exon 3 of 14		NP_001231533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.535A>G	p.Thr179Ala	missense_variant	Exon 3 of 14	1	NM_001197293.3	ENSP00000427985.2
DPYSL2	ENST00000311151.9	c.220A>G	p.Thr74Ala	missense_variant	Exon 3 of 14	1		ENSP00000309539.5
DPYSL2	ENST00000523027.1	c.112A>G	p.Thr38Ala	missense_variant	Exon 3 of 14	2		ENSP00000431117.1
DPYSL2	ENST00000493789.6	c.436A>G	p.Thr146Ala	missense_variant	Exon 3 of 3	4		ENSP00000427954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535A>G (p.T179A) alteration is located in exon 3 (coding exon 3) of the DPYSL2 gene. This alteration results from a A to G substitution at nucleotide position 535, causing the threonine (T) at amino acid position 179 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;.;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	.;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0090	.;D;D;D
Sift4G	Uncertain	0.0040	.;D;D;D
Polyphen		0.94	.;.;P;.
Vest4		0.74, 0.74
MutPred		0.60		.;.;Loss of phosphorylation at T74 (P = 0.1653);.;
MVP		0.94
MPC		1.9
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-26441406;