rs1057516879

chr17-3476161-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000049.4(ASPA):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000248 in 1,613,106 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ASPA NM_000049.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.50

Genes affected

ASPA (HGNC:756): (aspartoacylase) This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

SPATA22 (HGNC:30705): (spermatogenesis associated 22) Predicted to be involved in regulation of meiotic cell cycle. Predicted to act upstream of or within several processes, including fertilization; gamete generation; and meiosis I cell cycle process. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000049.4 (ASPA) was described as [Pathogenic] in ClinVar as 2826210
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3476161-T-C is Pathogenic according to our data. Variant chr17-3476161-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3476161-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPA	NM_000049.4	c.2T>C	p.Met1?	start_lost	1/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3	c.2T>C	p.Met1?	start_lost	1/6	1	NM_000049.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251148 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135764

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460894 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726828

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 15, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile16 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8659549, 12638939). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 370934). Disruption of the initiator codon has been observed in individual(s) with Canavan disease (PMID: 20129749). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects the initiator methionine of the ASPA mRNA. The next in-frame methionine is located at codon 82. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 18, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.97	.;D;D
Vest4		0.97, 0.98
MutPred		1.0		Gain of glycosylation at M1 (P = 0.0308);Gain of glycosylation at M1 (P = 0.0308);Gain of glycosylation at M1 (P = 0.0308);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057516879; hg19: chr17-3379455;