Variant chr2-26924957-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_020134.4(DPYSL5):c.332A>C(p.Asp111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DPYSL5
NM_020134.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30307248).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYSL5	NM_020134.4 link	c.332A>C	p.Asp111Ala	missense_variant	3/13	ENST00000288699.11	NP_064519.2	Q9BPU6
DPYSL5	NM_001253723.2 link	c.332A>C	p.Asp111Ala	missense_variant	3/13		NP_001240652.1	Q9BPU6
DPYSL5	NM_001253724.2 link	c.332A>C	p.Asp111Ala	missense_variant	3/13		NP_001240653.1	Q9BPU6
DPYSL5	XM_024453007.2 link	c.332A>C	p.Asp111Ala	missense_variant	3/13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11 link	c.332A>C	p.Asp111Ala	missense_variant	3/13	1	NM_020134.4	ENSP00000288699.6		Q9BPU6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251252

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727232

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ritscher-Schinzel syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The observed missense c.332A>C(p.Asp111Ala) variant in DPYSL5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.002% in gnomAD Exomes database. This variant has not been submitted to the ClinVar database. Computational evidence (Polyphen - Benign, SIFT -Tolerated and MutationTaster -disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Asp111Ala in DPYSL5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 111 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

.;T;T;T;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.059

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

T;.;.;T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.30

T;T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.0

.;L;L;.;L;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.6

D;N;N;D;.;D

REVEL

Benign

0.24

Sift

Benign

0.24

T;T;T;T;.;T

Sift4G

Benign

0.41

T;T;T;T;T;T

Polyphen

0.0

.;B;B;.;B;.

Vest4

0.45, 0.45

MutPred

0.42

Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);

MVP

0.41

MPC

1.3

ClinPred

0.42

GERP RS

5.0

Varity_R

0.39

gMVP

0.85

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

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