rs193302879

Variant names:

• chr11-119027811-G-A
• rs193302879
• ENST00000330775.9:c.443C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-119027811-G-A
• chr11-119027811-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001164278.2(SLC37A4):​c.443C>T​(p.Ala148Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,098 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC37A4 NM_001164278.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.36

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity G6PT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001164278.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 11-119027811-G-A is Pathogenic according to our data. Variant chr11-119027811-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68279.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119027811-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.443C>T	p.Ala148Val	missense_variant	Exon 5 of 12		NP_001157750.1
SLC37A4	NM_001164277.2	c.443C>T	p.Ala148Val	missense_variant	Exon 5 of 11		NP_001157749.1
SLC37A4	NM_001164280.2	c.443C>T	p.Ala148Val	missense_variant	Exon 3 of 9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.443C>T	p.Ala148Val	missense_variant	Exon 4 of 10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000835 AC: 2 AN: 239594 Hom.: 0 AF XY: 0.00000769 AC XY: 1 AN XY: 130002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457098 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:1

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 148 of the SLC37A4 protein (p.Ala148Val). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC37A4 protein function. ClinVar contains an entry for this variant (Variation ID: 68279). This missense change has been observed in individual(s) with glycogen storage disease, and is considered to be common in Korean subpopulation (PMID: 15953877, 28224773). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs193302879, gnomAD 0.01%). -

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.41	T;T;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.85	D;D;D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.0070	D;D;D;D
Vest4		0.95
MVP		0.44
MPC		0.17
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.92

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

Other links and lift over

dbSNP: rs193302879; hg19: chr11-118898521;