Genetic Variant NM_020134.4:c.347G>C (chr2-26924972-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_020134.4(DPYSL5):c.347G>C(p.Cys116Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DPYSL5
NM_020134.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.42

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL5	NM_020134.4 link	c.347G>C	p.Cys116Ser	missense_variant	Exon 3 of 13	ENST00000288699.11	NP_064519.2	Q9BPU6
DPYSL5	NM_001253723.2 link	c.347G>C	p.Cys116Ser	missense_variant	Exon 3 of 13		NP_001240652.1	Q9BPU6
DPYSL5	NM_001253724.2 link	c.347G>C	p.Cys116Ser	missense_variant	Exon 3 of 13		NP_001240653.1	Q9BPU6
DPYSL5	XM_024453007.2 link	c.347G>C	p.Cys116Ser	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.347G>C	p.Cys116Ser	missense_variant	Exon 3 of 13	1	NM_020134.4	ENSP00000288699.6		Q9BPU6

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251246

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.347G>C (p.C116S) alteration is located in exon 3 (coding exon 2) of the DPYSL5 gene. This alteration results from a G to C substitution at nucleotide position 347, causing the cysteine (C) at amino acid position 116 to be replaced by a serine (S). 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

0.23

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.30

.;T;T;T;T;.

Eigen

Benign

-0.088

Eigen_PC

Benign

0.093

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;.;.;D;T;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.49

T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.84

.;L;L;.;L;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.0

N;N;N;N;.;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.017

D;D;D;D;.;D

Sift4G

Uncertain

0.043

D;D;D;D;D;T

Polyphen

0.0010

.;B;B;.;B;.

Vest4

0.53, 0.53

MutPred

0.69

Gain of disorder (P = 8e-04);Gain of disorder (P = 8e-04);Gain of disorder (P = 8e-04);Gain of disorder (P = 8e-04);Gain of disorder (P = 8e-04);Gain of disorder (P = 8e-04);

MVP

0.36

MPC

1.0

ClinPred

0.16

GERP RS

5.0

Varity_R

0.50

gMVP

0.94

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