Genetic Variant DPYSL5:p.Lys123Arg (chr2-26924993-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020134.4(DPYSL5):c.368A>G(p.Lys123Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPYSL5
NM_020134.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94

Variant links:

Genes affected

DPYSL5 (HGNC:20637): (dihydropyrimidinase like 5) This gene encodes a member of the CRMP (collapsing response mediator protein) family thought to be involved in neural development. Antibodies to the encoded protein were found in some patients with neurologic symptoms who had paraneoplastic syndrome. A pseudogene of this gene is found on chromosome 11. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Dec 2011]

DPYSL5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL5	NM_020134.4 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 3 of 13	ENST00000288699.11	NP_064519.2	Q9BPU6
DPYSL5	NM_001253723.2 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 3 of 13		NP_001240652.1	Q9BPU6
DPYSL5	NM_001253724.2 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 3 of 13		NP_001240653.1	Q9BPU6
DPYSL5	XM_024453007.2 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 3 of 13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11 link	c.368A>G	p.Lys123Arg	missense_variant	Exon 3 of 13	1	NM_020134.4	ENSP00000288699.6		Q9BPU6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368A>G (p.K123R) alteration is located in exon 3 (coding exon 2) of the DPYSL5 gene. This alteration results from a A to G substitution at nucleotide position 368, causing the lysine (K) at amino acid position 123 to be replaced by an arginine (R). 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

Benign

0.093

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;D;D;T;D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;.;.;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.9

.;M;M;.;M;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.9

D;N;N;D;.;D

REVEL

Uncertain

0.60

Sift

Benign

0.044

D;T;T;T;.;T

Sift4G

Benign

0.065

T;T;T;T;T;T

Polyphen

0.73

.;P;P;.;P;.

Vest4

0.63

MVP

0.75

MPC

1.5

ClinPred

0.99

GERP RS

5.0

Varity_R

0.62

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over