rs377217076

Variant names:

• chr17-3498916-C-A
• rs377217076
• NM_000049.4:c.770C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-3498916-C-A
• chr17-3498916-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000049.4(ASPA):​c.770C>A​(p.Pro257His) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,044 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P257R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87
• Publications: 0 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-3498916-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430157.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	NM_000049.4	MANE Select	c.770C>A	p.Pro257His	missense	Exon 6 of 6	NP_000040.1
	ASPA	NM_001128085.1		c.770C>A	p.Pro257His	missense	Exon 7 of 7	NP_001121557.1
	SPATA22	NM_001321337.2		c.-74+14496G>T		intron	N/A	NP_001308266.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	ENST00000263080.3	TSL:1 MANE Select	c.770C>A	p.Pro257His	missense	Exon 6 of 6	ENSP00000263080.2
	ASPA	ENST00000456349.6	TSL:1	c.770C>A	p.Pro257His	missense	Exon 7 of 7	ENSP00000409976.2
	SPATA22	ENST00000541913.5	TSL:2	c.-74+14496G>T		intron	N/A	ENSP00000441920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453044 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721726

African (AFR) AF: 0.00 AC: 0 AN: 33096

American (AMR) AF: 0.00 AC: 0 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 84934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106728

Other (OTH) AF: 0.00 AC: 0 AN: 59976

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.9
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.072	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.57		Loss of ubiquitination at K253 (P = 0.121)
MVP		0.99
MPC		0.40
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.61
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs377217076; hg19: chr17-3402210;