rs377217076

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.87

Publications

0 publications found

Variant links:

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]

ASPA links:

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

SPATA22 links:

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ACMG classification

Classification was made for transcript

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 id is 430157.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPA	NM_000049.4 link	c.770C>A	p.Pro257His	missense_variant	Exon 6 of 6	ENST00000263080.3	NP_000040.1	P45381Q6FH48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASPA	ENST00000263080.3 link	c.770C>A	p.Pro257His	missense_variant	Exon 6 of 6	1	NM_000049.4	ENSP00000263080.2	P45381
ASPA	ENST00000456349.6 link	c.770C>A	p.Pro257His	missense_variant	Exon 7 of 7	1		ENSP00000409976.2	P45381
SPATA22	ENST00000541913.5 link	c.-74+14496G>T		intron_variant	Intron 1 of 8	2		ENSP00000441920.1	F5GWB9
SPATA22	ENST00000570318.1 link	c.-74+14695G>T		intron_variant	Intron 1 of 1	2		ENSP00000459147.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721726

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33096

American (AMR)

AF:

0.00

AC:

AN:

43802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

84934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106728

Other (OTH)

AF:

0.00

AC:

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

.;T

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M

PhyloP100

3.9

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.072

T;T

Polyphen

1.0

D;D

Vest4

0.47

MutPred

0.57

Loss of ubiquitination at K253 (P = 0.121);Loss of ubiquitination at K253 (P = 0.121);

MVP

0.99

MPC

0.40

ClinPred

1.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over