NM_020134.4:c.139G>A

Variant names:

• chr2-26898638-G-A
• rs1558337060
• NM_020134.4:c.139G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Ritscher-Schinzel syndrome 4

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020134.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL5	NM_020134.4	MANE Select	c.139G>A	p.Gly47Arg	missense	Exon 2 of 13	NP_064519.2
	DPYSL5	NM_001253723.2		c.139G>A	p.Gly47Arg	missense	Exon 2 of 13	NP_001240652.1	Q9BPU6
	DPYSL5	NM_001253724.2		c.139G>A	p.Gly47Arg	missense	Exon 2 of 13	NP_001240653.1	Q9BPU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL5	ENST00000288699.11	TSL:1 MANE Select	c.139G>A	p.Gly47Arg	missense	Exon 2 of 13	ENSP00000288699.6	Q9BPU6
	DPYSL5	ENST00000401478.5	TSL:1	c.139G>A	p.Gly47Arg	missense	Exon 2 of 13	ENSP00000385549.1	Q9BPU6
	DPYSL5	ENST00000614712.4	TSL:5	c.139G>A	p.Gly47Arg	missense	Exon 2 of 13	ENSP00000481305.1	Q9BPU6

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dandy-Walker syndrome (1)
-	1	-	not specified (1)
-	1	-	Ritscher-Schinzel syndrome 1;C5680766:Syndrome with a Dandy-Walker malformation as major feature (1)
1	-	-	Ritscher-Schinzel syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.69		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
Mutation Taster		=32/68	disease causing

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

Other links and lift over

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