rs144321760

Variant names:

• chr17-3483575-T-C
• rs144321760
• NM_000049.4:c.509T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP2 PP5 BP4

The NM_000049.4(ASPA):​c.509T>C​(p.Ile170Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000709 in 1,613,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9
• Conservation: PhyloP100: 6.24
• Publications: 13 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000049.4
• 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.
• PP5: Variant 17-3483575-T-C is Pathogenic according to our data. Variant chr17-3483575-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 322633.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3882036). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000049.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	NM_000049.4	MANE Select	c.509T>C	p.Ile170Thr	missense	Exon 3 of 6	NP_000040.1	Q6FH48
	ASPA	NM_001128085.1		c.509T>C	p.Ile170Thr	missense	Exon 4 of 7	NP_001121557.1	P45381
	SPATA22	NM_001321337.2		c.-73-14177A>G		intron	N/A	NP_001308266.1	A0A140VJV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	ENST00000263080.3	TSL:1 MANE Select	c.509T>C	p.Ile170Thr	missense	Exon 3 of 6	ENSP00000263080.2	P45381
	ASPA	ENST00000456349.6	TSL:1	c.509T>C	p.Ile170Thr	missense	Exon 4 of 7	ENSP00000409976.2	P45381
	ASPA	ENST00000858436.1		c.509T>C	p.Ile170Thr	missense	Exon 4 of 7	ENSP00000528495.1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251418 AF XY: 0.000302

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000714 AC: 1044 AN: 1461254 Hom.: 1 Cov.: 31 AF XY: 0.000619 AC XY: 450 AN XY: 727000

African (AFR) AF: 0.0000896 AC: 3 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000897 AC: 997 AN: 1111440

Other (OTH) AF: 0.000547 AC: 33 AN: 60372

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74396

African (AFR) AF: 0.0000964 AC: 4 AN: 41474

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000786 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.00136

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	5	-	Spongy degeneration of central nervous system (6)
-	3	-	not provided (3)
1	-	-	Canavan Disease, Familial Form (1)
-	1	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.39	T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.9	L
PhyloP100		6.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.037	D
Polyphen		0.21	B
Vest4		0.55
MVP		0.93
MPC		0.20
ClinPred		0.21	T
GERP RS		5.4
Varity_R		0.56
gMVP		0.79
Mutation Taster		=76/24	polymorphism

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: rs144321760; hg19: chr17-3386869; COSMIC: COSV53982040;