rs201036248

Variant names:

• chr11-119027787-G-A
• rs201036248
• NM_001164277.2:c.467C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001164277.2(SLC37A4):​c.467C>T​(p.Ala156Val) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,611,414 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A156A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: SLC37A4 NM_001164277.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 5.24
• Publications: 3 publications found

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]

SLC37A4 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation, type IIw

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• glycogen storage disease Ib

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• glycogen storage disease type 1 due to SLC37A4 mutation

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001164277.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011417329).
• BP6: Variant 11-119027787-G-A is Benign according to our data. Variant chr11-119027787-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215177.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00205 (312/152362) while in subpopulation NFE AF = 0.00341 (232/68040). AF 95% confidence interval is 0.00305. There are 1 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164277.2	c.467C>T	p.Ala156Val	missense_variant	Exon 5 of 11	ENST00000642844.3	NP_001157749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.467C>T	p.Ala156Val	missense_variant	Exon 4 of 10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00166 AC: 403 AN: 243018 AF XY: 0.00163

Gnomad AFR exome AF: 0.000268

Gnomad AMR exome AF: 0.000773

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.00241 AC: 3514 AN: 1459052 Hom.: 9 Cov.: 34 AF XY: 0.00240 AC XY: 1744 AN XY: 725606

African (AFR) AF: 0.000239 AC: 8 AN: 33444

American (AMR) AF: 0.000589 AC: 26 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26078

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.000245 AC: 21 AN: 85830

European-Finnish (FIN) AF: 0.00355 AC: 189 AN: 53226

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00286 AC: 3171 AN: 1110648

Other (OTH) AF: 0.00151 AC: 91 AN: 60282

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00209 AC XY: 156 AN XY: 74504

African (AFR) AF: 0.000289 AC: 12 AN: 41590

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68040

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Apr 13, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22899091) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC37A4: BS2 -

Feb 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glucose-6-phosphate transport defect Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Glycogen storage disease, type I Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC37A4 NM_001164277.1 exon 4 p.Ala156Val (c.467C>T): This variant has been reported in the literature in 1 individual with features suggestive of a glycogen storage disease; of note, it was one of three SLC37A4 variants identified in this individual, determined to be in cis with one variant and of unknown phase with the other (Wang 2013 PMID:22899091). This variant is present in 0.4% (42/10624) of Finnish alleles and in 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-119027787-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:215177). Evolutionary conservation and computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:1

Aug 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC37A4 c.467C>T (p.Ala156Val) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 274424 control chromosomes, including 2 homozygotes (gnomAD). The variant was found predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC37A4 causing Glycogen Storage Disease Type Ib (0.0012), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.467C>T has been reported in the literature occuring in cis with variant c.572C>T [p.Pro191Arg] in one individual affected with Glycogen Storage Disease Type Ib (Wang_2013). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease Type Ib. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22899091). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.15	T;T;T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T;T;T;T
PhyloP100		5.2
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.64	T;T;T;T
Vest4		0.42
MVP		0.33
MPC		0.027
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.87
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201036248; hg19: chr11-118898497;