NM_020134.4:c.121G>A

Variant names:

• chr2-26898620-G-A
• rs866373727
• NM_020134.4:c.121G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_020134.4(DPYSL5):​c.121G>A​(p.Glu41Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPYSL5 NM_020134.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:2
• Conservation: PhyloP100: 3.94
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26898620-G-A is Pathogenic according to our data. Variant chr2-26898620-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1184280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.121G>A	p.Glu41Lys	missense	Exon 2 of 13	NP_064519.2
	DPYSL5	NM_001253723.2		c.121G>A	p.Glu41Lys	missense	Exon 2 of 13	NP_001240652.1	Q9BPU6
	DPYSL5	NM_001253724.2		c.121G>A	p.Glu41Lys	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.121G>A	p.Glu41Lys	missense	Exon 2 of 13	ENSP00000288699.6	Q9BPU6
	DPYSL5	ENST00000401478.5	TSL:1	c.121G>A	p.Glu41Lys	missense	Exon 2 of 13	ENSP00000385549.1	Q9BPU6
	DPYSL5	ENST00000614712.4	TSL:5	c.121G>A	p.Glu41Lys	missense	Exon 2 of 13	ENSP00000481305.1	Q9BPU6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	2	-	not provided (3)
1	-	-	DPYSL5-related disorder (1)
1	-	-	Ritscher-Schinzel syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.51	N
PhyloP100		3.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Benign	0.062	T
Sift4G	Uncertain	0.057	T
Polyphen		0.012	B
Vest4		0.40
MutPred		0.65		Gain of methylation at E41 (P = 0.0206)
MVP		0.54
MPC		1.1
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.60
gMVP		0.94
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs866373727; hg19: chr2-27121488; COSMIC: COSV56512143;