NM_000049.4:c.604G>C

Variant names:

• chr17-3489312-G-C
• rs147763700
• NM_000049.4:c.604G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000049.4(ASPA):​c.604G>C​(p.Ala202Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,796 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A202V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.29
• Publications: 2 publications found

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]

SPATA22 Gene-Disease associations (from GenCC):

• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.47868 (below the threshold of 3.09). Trascript score misZ: 1.2423 (below the threshold of 3.09). GenCC associations: The gene is linked to Canavan disease, mild Canavan disease, severe Canavan disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 17-3489312-G-C is Pathogenic according to our data. Variant chr17-3489312-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488070.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPA	NM_000049.4	c.604G>C	p.Ala202Pro	missense_variant	Exon 4 of 6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3	c.604G>C	p.Ala202Pro	missense_variant	Exon 4 of 6	1	NM_000049.4	ENSP00000263080.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111404

Other (OTH) AF: 0.0000166 AC: 1 AN: 60344

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:1

Sep 28, 2017

Genomics For Life

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the ACMG Guidelines 2015, the ASPA c.604G>C; p.Ala202Pro variant was originally classified as a Variant of Unknown Significance. Segregation analysis indicates that the ASPA c.820G>A; p.Gly274Arg variant is carried by the proband's father and the ASPA c.604G>C; p.Ala202Pro variant by the proband's mother indicating the two variants occur in trans. Based on this segregation data and the ACMG Guidelines 2015, the ASPA c.604G>C; p.Ala202Pro variant is classified as a Likely Pathogenic (Class 4 in the IARC 5-Class system) variant (Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation; Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium; For recessive disorders, detected in trans with a pathogenic variant; Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease; Multiple lines of computational evidence support a deleterious effect on the gene or gene product; Patient's phenotype or family history is highly specific for a disease with a single genetic aetiology). The ASPA c.604G>C; p.Ala202Pro variant occurs within the N-terminal domain of the protein (Bitto, Bingman et al. 2007). Approximately 60% of known missense mutations of ASPA are located within the N-terminal domain (Bitto, Bingman et al. 2007). The ASPA c.604G>C; p.Ala202Pro variant substitutes a nonpolar hydrophobic amino acid Proline for a nonpolar hydrophobic amino acid Alanine. Proline (Pro) is unique among the 20 naturally occurring amino acid residues (Bajaj, Madhusudhan et al. 2007). Pro lacks an amide proton and the main chain amide N is incapable of forming H-bonds (hydrogen bonds) (Bajaj, Madhusudhan et al. 2007). Hence, substituting a residue involved in a main chain H-bond with Pro could destabilize the protein (Bajaj, Madhusudhan et al. 2007). The rigid pyrrolidine ring of Pro constrains the main chain dihedral angle Phi to a narrow range of values close to -65 degrees (Bajaj, Madhusudhan et al. 2007). It has also been observed that Pro restricts the conformation of the residue preceding it in a protein sequence (Bajaj, Madhusudhan et al. 2007).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.065	T;T
Sift4G	Benign	0.14	T;T
Vest4		0.84
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.93
Mutation Taster		=34/66	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs147763700; hg19: chr17-3392606;