chr2-26924957-A-C

Position:

• chr2-26924957-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 5P and 5B. PM2 PP2 PP5_Moderate BP4 BS2

The NM_020134.4(DPYSL5):​c.332A>C​(p.Asp111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DPYSL5 NM_020134.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 0 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.
• PP5: Variant 2-26924957-A-C is Pathogenic according to our data. Variant chr2-26924957-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3362820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30307248). . Strength limited to SUPPORTING due to the PP5.
• 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.332A>C	p.Asp111Ala	missense_variant	3/13	ENST00000288699.11	NP_064519.2
DPYSL5	NM_001253723.2	c.332A>C	p.Asp111Ala	missense_variant	3/13		NP_001240652.1
DPYSL5	NM_001253724.2	c.332A>C	p.Asp111Ala	missense_variant	3/13		NP_001240653.1
DPYSL5	XM_024453007.2	c.332A>C	p.Asp111Ala	missense_variant	3/13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11	c.332A>C	p.Asp111Ala	missense_variant	3/13	1	NM_020134.4	ENSP00000288699	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251252 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ritscher-Schinzel syndrome 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The frameshift variant c.11712del (p.Gln3905ArgfsTer5) in the HYDIN gene has been previously reported with Joubert syndrome (Pal LR et al., 2017). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic. This variant causes a frameshift starting with codon Glutamine 3905, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Gln3905ArgfsTer5. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Further studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likley pathogenic. The variant has a high internal frequency in our database and this could be due to pseudogene interference which impedes accurate variant assessment. In the absence of another reportable variant in HYDIN gene, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	.;T;T;T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.059
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	T;.;.;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.0	.;L;L;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D;N;N;D;.;D
REVEL	Benign	0.24
Sift	Benign	0.24	T;T;T;T;.;T
Sift4G	Benign	0.41	T;T;T;T;T;T
Polyphen		0.0	.;B;B;.;B;.
Vest4		0.45, 0.45
MutPred		0.42		Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);Gain of catalytic residue at D111 (P = 0.07);
MVP		0.41
MPC		1.3
ClinPred		0.42	T
GERP RS		5.0
Varity_R		0.39
gMVP		0.85

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: rs762975695; hg19: chr2-27147825;