NM_004172.5:c.657G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004172.5(SLC1A3):​c.657G>C​(p.Glu219Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,030 control chromosomes in the GnomAD database, including 474 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 86 hom., cov: 33)
Exomes 𝑓: 0.012 ( 388 hom. )

Consequence

SLC1A3
NM_004172.5 missense

Scores

3
15

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.467

Publications

26 publications found
Variant links:
Genes affected
SLC1A3 (HGNC:10941): (solute carrier family 1 member 3) This gene encodes a member of a member of a high affinity glutamate transporter family. This gene functions in the termination of excitatory neurotransmission in central nervous system. Mutations are associated with episodic ataxia, Type 6. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2014]
SLC1A3-AS1 (HGNC:56374): (SLC1A3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0015866756).
BP6
Variant 5-36676981-G-C is Benign according to our data. Variant chr5-36676981-G-C is described in ClinVar as [Benign]. Clinvar id is 130326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC1A3NM_004172.5 linkc.657G>C p.Glu219Asp missense_variant Exon 6 of 10 ENST00000265113.9 NP_004163.3 P43003-1A0A024R050Q8N169

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC1A3ENST00000265113.9 linkc.657G>C p.Glu219Asp missense_variant Exon 6 of 10 1 NM_004172.5 ENSP00000265113.4 P43003-1

Frequencies

GnomAD3 genomes
AF:
0.0195
AC:
2971
AN:
152144
Hom.:
86
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0292
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0704
Gnomad ASJ
AF:
0.0251
Gnomad EAS
AF:
0.00154
Gnomad SAS
AF:
0.0143
Gnomad FIN
AF:
0.00273
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.00660
Gnomad OTH
AF:
0.0182
GnomAD2 exomes
AF:
0.0247
AC:
6215
AN:
251238
AF XY:
0.0209
show subpopulations
Gnomad AFR exome
AF:
0.0281
Gnomad AMR exome
AF:
0.115
Gnomad ASJ exome
AF:
0.0295
Gnomad EAS exome
AF:
0.000653
Gnomad FIN exome
AF:
0.00374
Gnomad NFE exome
AF:
0.00667
Gnomad OTH exome
AF:
0.0197
GnomAD4 exome
AF:
0.0115
AC:
16880
AN:
1461768
Hom.:
388
Cov.:
31
AF XY:
0.0114
AC XY:
8266
AN XY:
727194
show subpopulations
African (AFR)
AF:
0.0281
AC:
941
AN:
33468
American (AMR)
AF:
0.107
AC:
4788
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.0280
AC:
731
AN:
26136
East Asian (EAS)
AF:
0.00149
AC:
59
AN:
39696
South Asian (SAS)
AF:
0.0184
AC:
1587
AN:
86256
European-Finnish (FIN)
AF:
0.00440
AC:
235
AN:
53406
Middle Eastern (MID)
AF:
0.0288
AC:
166
AN:
5768
European-Non Finnish (NFE)
AF:
0.00679
AC:
7546
AN:
1111932
Other (OTH)
AF:
0.0137
AC:
827
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
928
1857
2785
3714
4642
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
374
748
1122
1496
1870
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0195
AC:
2975
AN:
152262
Hom.:
86
Cov.:
33
AF XY:
0.0197
AC XY:
1467
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.0292
AC:
1211
AN:
41540
American (AMR)
AF:
0.0706
AC:
1080
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.0251
AC:
87
AN:
3472
East Asian (EAS)
AF:
0.00154
AC:
8
AN:
5184
South Asian (SAS)
AF:
0.0141
AC:
68
AN:
4822
European-Finnish (FIN)
AF:
0.00273
AC:
29
AN:
10618
Middle Eastern (MID)
AF:
0.0170
AC:
5
AN:
294
European-Non Finnish (NFE)
AF:
0.00660
AC:
449
AN:
68012
Other (OTH)
AF:
0.0180
AC:
38
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
140
280
419
559
699
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
32
64
96
128
160
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0100
Hom.:
15
Bravo
AF:
0.0247
TwinsUK
AF:
0.00485
AC:
18
ALSPAC
AF:
0.00727
AC:
28
ESP6500AA
AF:
0.0286
AC:
126
ESP6500EA
AF:
0.00640
AC:
55
ExAC
AF:
0.0205
AC:
2491
Asia WGS
AF:
0.00808
AC:
28
AN:
3478
EpiCase
AF:
0.00742
EpiControl
AF:
0.00883

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Jul 15, 2019
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 05, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21233784, 33126486, 32819603) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:2
-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 01, 2018
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Episodic ataxia type 6 Benign:1
Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.16
.;T;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.61
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.55
T;T;T
MetaRNN
Benign
0.0016
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
.;N;N
PhyloP100
0.47
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.46
.;N;N
REVEL
Benign
0.037
Sift
Benign
0.27
.;T;T
Sift4G
Benign
0.46
T;T;T
Polyphen
0.0010
.;B;.
Vest4
0.071
MutPred
0.22
.;Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MPC
0.41
ClinPred
0.011
T
GERP RS
-0.25
PromoterAI
0.061
Neutral
Varity_R
0.053
gMVP
0.63
Mutation Taster
=89/11
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

Publications

Other links and lift over

dbSNP: rs2032892; hg19: chr5-36677083; API