rs34203644

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001164278.2(SLC37A4):​c.593A>T​(p.Asn198Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00492 in 1,613,926 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N198S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 33)
Exomes 𝑓: 0.0050 ( 23 hom. )

Consequence

SLC37A4
NM_001164278.2 missense

Scores

1
4
6

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.77
Variant links:
Genes affected
SLC37A4 (HGNC:4061): (solute carrier family 37 member 4) This gene regulates glucose-6-phosphate transport from the cytoplasm to the lumen of the endoplasmic reticulum, in order to maintain glucose homeostasis. It also plays a role in ATP-mediated calcium sequestration in the lumen of the endoplasmic reticulum. Mutations in this gene have been associated with various forms of glycogen storage disease. Alternative splicing in this gene results in multiple transcript variants.[provided by RefSeq, Aug 2009]

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=0.015274823).
BP6
Variant 11-119027660-T-A is Benign according to our data. Variant chr11-119027660-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 139188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119027660-T-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00387 (590/152306) while in subpopulation AMR AF = 0.00797 (122/15298). AF 95% confidence interval is 0.00682. There are 4 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC37A4NM_001164278.2 linkc.593A>T p.Asn198Ile missense_variant Exon 6 of 12 NP_001157750.1 O43826-2A0A024R3L1
SLC37A4NM_001164277.2 linkc.593A>T p.Asn198Ile missense_variant Exon 6 of 11 NP_001157749.1 O43826-1A0A024R3H9A8K0S7
SLC37A4NM_001164280.2 linkc.593A>T p.Asn198Ile missense_variant Exon 4 of 9 NP_001157752.1 O43826-1A0A024R3H9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC37A4ENST00000330775.9 linkc.593A>T p.Asn198Ile missense_variant Exon 5 of 10 5 ENSP00000476242.2 U3KPU7

Frequencies

GnomAD3 genomes
AF:
0.00388
AC:
590
AN:
152188
Hom.:
4
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00109
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00799
Gnomad ASJ
AF:
0.00374
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000847
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00572
Gnomad OTH
AF:
0.00478
GnomAD2 exomes
AF:
0.00363
AC:
903
AN:
249060
AF XY:
0.00366
show subpopulations
Gnomad AFR exome
AF:
0.00116
Gnomad AMR exome
AF:
0.00493
Gnomad ASJ exome
AF:
0.00368
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000789
Gnomad NFE exome
AF:
0.00549
Gnomad OTH exome
AF:
0.00579
GnomAD4 exome
AF:
0.00503
AC:
7349
AN:
1461620
Hom.:
23
Cov.:
32
AF XY:
0.00493
AC XY:
3581
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.000866
AC:
29
AN:
33480
Gnomad4 AMR exome
AF:
0.00523
AC:
234
AN:
44710
Gnomad4 ASJ exome
AF:
0.00329
AC:
86
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39692
Gnomad4 SAS exome
AF:
0.000255
AC:
22
AN:
86218
Gnomad4 FIN exome
AF:
0.00120
AC:
64
AN:
53402
Gnomad4 NFE exome
AF:
0.00595
AC:
6614
AN:
1111840
Gnomad4 Remaining exome
AF:
0.00490
AC:
296
AN:
60374
Heterozygous variant carriers
0
394
789
1183
1578
1972
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
254
508
762
1016
1270
<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:
0.00387
AC:
590
AN:
152306
Hom.:
4
Cov.:
33
AF XY:
0.00369
AC XY:
275
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00108
AC:
0.00108267
AN:
0.00108267
Gnomad4 AMR
AF:
0.00797
AC:
0.0079749
AN:
0.0079749
Gnomad4 ASJ
AF:
0.00374
AC:
0.00374424
AN:
0.00374424
Gnomad4 EAS
AF:
0.000193
AC:
0.000192827
AN:
0.000192827
Gnomad4 SAS
AF:
0.000207
AC:
0.000207039
AN:
0.000207039
Gnomad4 FIN
AF:
0.000847
AC:
0.000847458
AN:
0.000847458
Gnomad4 NFE
AF:
0.00572
AC:
0.00571907
AN:
0.00571907
Gnomad4 OTH
AF:
0.00473
AC:
0.00473485
AN:
0.00473485
Heterozygous variant carriers
0
34
69
103
138
172
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00477
Hom.:
4
Bravo
AF:
0.00396
TwinsUK
AF:
0.00485
AC:
18
ALSPAC
AF:
0.00649
AC:
25
ESP6500AA
AF:
0.00120
AC:
5
ESP6500EA
AF:
0.00618
AC:
52
ExAC
AF:
0.00363
AC:
439
EpiCase
AF:
0.00649
EpiControl
AF:
0.00711

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:8
May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SLC37A4: BS2 -

Oct 09, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

Apr 19, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary:The c.593A>T in SLC37A4 gene is a missense change that alters a conserved nucleotide and 2/4 in silico tools predict benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.36% exclusively in individuals of European descent (0.53%), including 2 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in SLC37A4 gene (0.12%). The variant of interest has been reported in three GSD1b patients (Zappu_2010) who also carried a splice-site mutation in homozygous state, strongly suggesting for benign outcome. In functional studies the variant had normal G6P transport activity (Chen, 2010). In addition, the variant has been reported as Benign/Polymorphism by a clinical laboratory and published reports (Zappu, 2010) Taking together, the variant has been classified as Benign. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Benign:2
Feb 02, 2017
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 29, 2013
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glucose-6-phosphate transport defect Benign:2
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 16, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Pathogenic
0.17
CADD
Benign
23
DANN
Benign
0.85
DEOGEN2
Benign
0.40
T;T;T;T
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
.;D;D;D
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.015
T;T;T;T
PrimateAI
Uncertain
0.55
T
Sift4G
Uncertain
0.012
D;D;D;D
Vest4
0.75
MVP
0.58
MPC
0.088
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.73
Mutation Taster
=74/26
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs34203644; hg19: chr11-118898370; API