2-26927265-A-T

Variant names:

• chr2-26927265-A-T
• rs1376319168
• NM_020134.4:c.433A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020134.4(DPYSL5):​c.433A>T​(p.Met145Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DPYSL5 NM_020134.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL5	NM_020134.4	c.433A>T	p.Met145Leu	missense_variant	Exon 4 of 13	ENST00000288699.11	NP_064519.2
DPYSL5	NM_001253723.2	c.433A>T	p.Met145Leu	missense_variant	Exon 4 of 13		NP_001240652.1
DPYSL5	NM_001253724.2	c.433A>T	p.Met145Leu	missense_variant	Exon 4 of 13		NP_001240653.1
DPYSL5	XM_024453007.2	c.433A>T	p.Met145Leu	missense_variant	Exon 4 of 13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11	c.433A>T	p.Met145Leu	missense_variant	Exon 4 of 13	1	NM_020134.4	ENSP00000288699.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250322 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461408 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;T;T;T;T;.
Eigen	Benign	-0.054
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.59	.;N;N;.;N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;N;N;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.37	T;T;T;T;.;T
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.017	.;B;B;.;B;.
Vest4		0.48, 0.48
MutPred		0.55		Loss of catalytic residue at V141 (P = 0.0215);Loss of catalytic residue at V141 (P = 0.0215);Loss of catalytic residue at V141 (P = 0.0215);Loss of catalytic residue at V141 (P = 0.0215);Loss of catalytic residue at V141 (P = 0.0215);Loss of catalytic residue at V141 (P = 0.0215);
MVP		0.54
MPC		1.6
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.62
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: rs1376319168; hg19: chr2-27150133;