chr2-26924937-C-A

Position:

• chr2-26924937-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020134.4(DPYSL5):​c.312C>A​(p.Asp104Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 6.8e-7 (0 hom.)
• Consequence: DPYSL5 NM_020134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DPYSL5. . Gene score misZ 3.0829 (greater than the threshold 3.09). Trascript score misZ 3.7328 (greater than threshold 3.09). GenCC has associacion of gene with Ritscher-Schinzel syndrome 4, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07828602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYSL5	NM_020134.4	c.312C>A	p.Asp104Glu	missense_variant	3/13	ENST00000288699.11	NP_064519.2
DPYSL5	NM_001253723.2	c.312C>A	p.Asp104Glu	missense_variant	3/13		NP_001240652.1
DPYSL5	NM_001253724.2	c.312C>A	p.Asp104Glu	missense_variant	3/13		NP_001240653.1
DPYSL5	XM_024453007.2	c.312C>A	p.Asp104Glu	missense_variant	3/13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11	c.312C>A	p.Asp104Glu	missense_variant	3/13	1	NM_020134.4	ENSP00000288699	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 18, 2023

Variant summary: DPYSL5 c.312C>A (p.Asp104Glu) results in a conservative amino acid change located in the Amidohydrolase-related domain (IPR006680) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251190 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.312C>A in individuals affected with Ritscher-Schinzel Syndrome 4 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.29
DEOGEN2	Benign	0.12	.;T;T;T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D;.;.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.078	T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.010	.;N;N;.;N;.
MutationTaster	Benign	0.68	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.94	N;N;N;N;.;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;B;B;.;B;.
Vest4		0.19, 0.19
MutPred		0.19		Gain of methylation at K105 (P = 0.0803);Gain of methylation at K105 (P = 0.0803);Gain of methylation at K105 (P = 0.0803);Gain of methylation at K105 (P = 0.0803);Gain of methylation at K105 (P = 0.0803);Gain of methylation at K105 (P = 0.0803);
MVP		0.17
MPC		0.78
ClinPred		0.12	T
GERP RS		2.2
Varity_R		0.47
gMVP		0.72

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: rs1664791781; hg19: chr2-27147805;