19-46775673-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005628.3(SLC1A5):​c.1463G>A​(p.Arg488His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SLC1A5
NM_005628.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.324
Variant links:
Genes affected
SLC1A5 (HGNC:10943): (solute carrier family 1 member 5) The SLC1A5 gene encodes a sodium-dependent neutral amino acid transporter that can act as a receptor for RD114/type D retrovirus (Larriba et al., 2001 [PubMed 11781704]).[supplied by OMIM, Jan 2011]
FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18274295).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC1A5NM_005628.3 linkc.1463G>A p.Arg488His missense_variant Exon 8 of 8 ENST00000542575.6 NP_005619.1 Q15758-1Q59ES3
SLC1A5NM_001145145.2 linkc.857G>A p.Arg286His missense_variant Exon 7 of 7 NP_001138617.1 Q15758-2
SLC1A5NM_001145144.2 linkc.779G>A p.Arg260His missense_variant Exon 8 of 8 NP_001138616.1 Q15758-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC1A5ENST00000542575.6 linkc.1463G>A p.Arg488His missense_variant Exon 8 of 8 1 NM_005628.3 ENSP00000444408.1 Q15758-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152100
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
249864
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135188
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000892
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461872
Hom.:
0
Cov.:
34
AF XY:
0.0000124
AC XY:
9
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152218
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000302
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1463G>A (p.R488H) alteration is located in exon 8 (coding exon 8) of the SLC1A5 gene. This alteration results from a G to A substitution at nucleotide position 1463, causing the arginine (R) at amino acid position 488 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.;T;.
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.29
N
LIST_S2
Benign
0.74
T;T;T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.18
T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.8
M;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-2.1
N;N;.;N
REVEL
Benign
0.14
Sift
Uncertain
0.012
D;D;.;D
Sift4G
Uncertain
0.024
D;D;D;D
Polyphen
0.97
D;.;.;.
Vest4
0.094
MutPred
0.39
Gain of catalytic residue at E490 (P = 0.0265);.;.;.;
MVP
0.84
MPC
0.72
ClinPred
0.80
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.056
gMVP
0.57

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: rs1291182407; hg19: chr19-47278930; COSMIC: COSV69466782; COSMIC: COSV69466782; API