2-26898638-G-A

Position:

• chr2-26898638-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_020134.4(DPYSL5):​c.139G>A​(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,890 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DPYSL5 NM_020134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:3
• Conservation: PhyloP100: 6.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• 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	c.139G>A	p.Gly47Arg	missense_variant	2/13	ENST00000288699.11	NP_064519.2
DPYSL5	NM_001253723.2	c.139G>A	p.Gly47Arg	missense_variant	2/13		NP_001240652.1
DPYSL5	NM_001253724.2	c.139G>A	p.Gly47Arg	missense_variant	2/13		NP_001240653.1
DPYSL5	XM_024453007.2	c.139G>A	p.Gly47Arg	missense_variant	2/13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11	c.139G>A	p.Gly47Arg	missense_variant	2/13	1	NM_020134.4	ENSP00000288699.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ritscher-Schinzel syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 22, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 20, 2024

Variant summary: DPYSL5 c.139G>A (p.Gly47Arg) results in a non-conservative amino acid change located in the D-HYD domain (IPR011778) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251466 control chromosomes. c.139G>A has been reported in a family affected with Dandy-Walker malformation (DWM) (originally described in Ritscher_1987). One of the sisters affected with DWM had this variant reported as de novo (Aldinger_2019), however this proband had a sibling affected with severe congenital heart defect that was not genotyped. Given the family history authors suspected gonadal mosaicism for inheritance (Jeanne_2022, Ritscher_1987). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence that this variant affects the normal function of the protein (Jeanne_ 2022). The following publications have been ascertained in the context of this evaluation (PMID: 31474318, 33894126, 3812597). ClinVar contains an entry for this variant (Variation ID: 632587). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Dandy-Walker syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Ritscher-Schinzel syndrome 1;C5680766:Syndrome with a Dandy-Walker malformation as major feature Uncertain:1

Uncertain significance, no assertion criteria provided

research

Dobyns Lab, Seattle Children's Research Institute

Feb 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;D;D;T;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;.;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.0	.;M;M;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.3	D;D;D;D;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;.
Vest4		0.67
MutPred		0.69		Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);Gain of solvent accessibility (P = 0.024);
MVP		0.66
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.76
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

LitVar

Other links and lift over

dbSNP: rs1558337060; hg19: chr2-27121506; COSMIC: COSV99982077;