17-3476162-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000049.4(ASPA):​c.3G>T​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASPA
NM_000049.4 start_lost

Scores

9
4
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.85
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000049.4 (ASPA) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-3476162-G-T is Pathogenic according to our data. Variant chr17-3476162-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813437.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ASPANM_000049.4 linkuse as main transcriptc.3G>T p.Met1? start_lost 1/6 ENST00000263080.3 NP_000040.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ASPAENST00000263080.3 linkuse as main transcriptc.3G>T p.Met1? start_lost 1/61 NM_000049.4 ENSP00000263080 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460832
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726802
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.48
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.023
T;T;T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;.;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.98
D
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-1.6
.;N;N
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.92
.;P;P
Vest4
0.94, 0.94
MutPred
1.0
Loss of disorder (P = 0.1492);Loss of disorder (P = 0.1492);Loss of disorder (P = 0.1492);
MVP
0.98
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.85
gMVP
0.82

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1597422213; hg19: chr17-3379456; COSMIC: COSV52152249; COSMIC: COSV52152249; API