rs80099330

Variant names:

• chr17-3481611-T-C
• rs80099330
• NM_000049.4:c.245T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000049.4(ASPA):​c.245T>C​(p.Met82Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,613,478 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.282
• Publications: 1 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0061526597).
• BP6: Variant 17-3481611-T-C is Benign according to our data. Variant chr17-3481611-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00361 (549/152270) while in subpopulation AFR AF = 0.0121 (501/41556). AF 95% confidence interval is 0.0112. There are 5 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.245T>C	p.Met82Thr	missense	Exon 2 of 6	NP_000040.1
	ASPA	NM_001128085.1		c.245T>C	p.Met82Thr	missense	Exon 3 of 7	NP_001121557.1
	SPATA22	NM_001321337.2		c.-73-12213A>G		intron	N/A	NP_001308266.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	ENST00000263080.3	TSL:1 MANE Select	c.245T>C	p.Met82Thr	missense	Exon 2 of 6	ENSP00000263080.2
	ASPA	ENST00000456349.6	TSL:1	c.245T>C	p.Met82Thr	missense	Exon 3 of 7	ENSP00000409976.2
	ASPA	ENST00000858436.1		c.245T>C	p.Met82Thr	missense	Exon 3 of 7	ENSP00000528495.1

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 548 AN: 152152 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

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: 0.00384

GnomAD2 exomes AF: 0.000929 AC: 233 AN: 250740 AF XY: 0.000642

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000396 AC: 579 AN: 1461208 Hom.: 3 Cov.: 31 AF XY: 0.000315 AC XY: 229 AN XY: 726890

African (AFR) AF: 0.0140 AC: 469 AN: 33456

American (AMR) AF: 0.000537 AC: 24 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000532 AC: 3 AN: 5640

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111780

Other (OTH) AF: 0.000613 AC: 37 AN: 60356

GnomAD4 genome AF: 0.00361 AC: 549 AN: 152270 Hom.: 5 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74462

African (AFR) AF: 0.0121 AC: 501 AN: 41556

American (AMR) AF: 0.00255 AC: 39 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00127 Hom.: 5

Bravo AF: 0.00412

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Spongy degeneration of central nervous system (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.2
DANN	Benign	0.87
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.28
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.16
Sift	Benign	0.57	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.092
MVP		0.72
MPC		0.078
ClinPred		0.00042	T
GERP RS		-3.3
Varity_R		0.13
gMVP		0.46
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80099330; hg19: chr17-3384905; COSMIC: COSV99036547;