rs193302889

chr11-119029289-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The ENST00000330775.9(SLC37A4):c.81T>A(p.Asn27Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,578 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N27S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 1.56

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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000330775.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 11-119029289-A-T is Pathogenic according to our data. Variant chr11-119029289-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68290.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, not_provided=1, Uncertain_significance=1}. Variant chr11-119029289-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC37A4	NM_001164277.2	c.81T>A	p.Asn27Lys	missense_variant	3/11	ENST00000642844.3
SLC37A4	NM_001164279.2	c.-172+103T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC37A4	ENST00000330775.9	c.81T>A	p.Asn27Lys	missense_variant	2/10	5		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249000 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135100

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 27 of the SLC37A4 protein (p.Asn27Lys). This variant is present in population databases (rs193302889, gnomAD 0.002%). This missense change has been observed in individuals with glycogen storage disease type 1b (PMID: 10923042, 28685844). It has also been observed to segregate with disease in related individuals. This variant is also known as c.250T>A. ClinVar contains an entry for this variant (Variation ID: 68290). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC37A4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 12444104). For these reasons, this variant has been classified as Pathogenic. -

Hepatomegaly;C0021051:Immunodeficiency;C0023530:Leukopenia;C0038002:Splenomegaly;C0853697:Neutropenia;C3806482:Recurrent respiratory infections Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 30, 2016

- -

Glycogen storage disease, type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	22
Dann	Benign	0.90
DEOGEN2	Uncertain	0.55	D;D;D
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.79	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Vest4		0.82
MVP		0.43
MPC		0.15
GERP RS		3.1
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: rs193302889; hg19: chr11-118899999;