NM_000049.4:c.693C>T

Variant names:

• chr17-3494408-C-T
• rs12948217
• NM_000049.4:c.693C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000049.4(ASPA):​c.693C>T​(p.Tyr231Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,609,446 control chromosomes in the GnomAD database, including 69,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5840 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63740 hom.)
• Consequence: ASPA NM_000049.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.453
• Publications: 43 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):

• genetic infertility

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 17-3494408-C-T is Benign according to our data. Variant chr17-3494408-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

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.693C>T	p.Tyr231Tyr	synonymous	Exon 5 of 6	NP_000040.1	Q6FH48
	ASPA	NM_001128085.1		c.693C>T	p.Tyr231Tyr	synonymous	Exon 6 of 7	NP_001121557.1	P45381
	SPATA22	NM_001321337.2		c.-74+19004G>A		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.693C>T	p.Tyr231Tyr	synonymous	Exon 5 of 6	ENSP00000263080.2	P45381
	ASPA	ENST00000456349.6	TSL:1	c.693C>T	p.Tyr231Tyr	synonymous	Exon 6 of 7	ENSP00000409976.2	P45381
	ASPA	ENST00000858436.1		c.693C>T	p.Tyr231Tyr	synonymous	Exon 6 of 7	ENSP00000528495.1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40950 AN: 151918 Hom.: 5841 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.260 AC: 65267 AN: 251370 AF XY: 0.263

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.0444

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.289 AC: 421404 AN: 1457410 Hom.: 63740 Cov.: 33 AF XY: 0.288 AC XY: 208910 AN XY: 725364

African (AFR) AF: 0.238 AC: 7961 AN: 33388

American (AMR) AF: 0.195 AC: 8701 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 7400 AN: 26090

East Asian (EAS) AF: 0.0432 AC: 1713 AN: 39684

South Asian (SAS) AF: 0.215 AC: 18549 AN: 86198

European-Finnish (FIN) AF: 0.330 AC: 17619 AN: 53366

Middle Eastern (MID) AF: 0.250 AC: 1440 AN: 5760

European-Non Finnish (NFE) AF: 0.308 AC: 341380 AN: 1108000

Other (OTH) AF: 0.276 AC: 16641 AN: 60208

GnomAD4 genome AF: 0.269 AC: 40958 AN: 152036 Hom.: 5840 Cov.: 32 AF XY: 0.267 AC XY: 19823 AN XY: 74306

African (AFR) AF: 0.237 AC: 9828 AN: 41468

American (AMR) AF: 0.216 AC: 3304 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3468

East Asian (EAS) AF: 0.0475 AC: 246 AN: 5184

South Asian (SAS) AF: 0.208 AC: 1004 AN: 4816

European-Finnish (FIN) AF: 0.323 AC: 3415 AN: 10558

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21298 AN: 67950

Other (OTH) AF: 0.266 AC: 560 AN: 2108

Alfa AF: 0.216 Hom.: 4130

Bravo AF: 0.258

Asia WGS AF: 0.135 AC: 470 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.306

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Spongy degeneration of central nervous system (5)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.5
DANN	Benign	0.72
PhyloP100		0.45
Mutation Taster		=98/2	polymorphism (auto)

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: rs12948217; hg19: chr17-3397702; COSMIC: COSV53981715;