rs201036248

chr11-119027787-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The ENST00000330775.9(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. 8/13 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 ENST00000330775.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 5.24

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 Benign. Variant got -7 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, 4 uncertain in ENST00000330775.9
• 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 id is 215177.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC37A4	NM_001164277.2	c.467C>T	p.Ala156Val	missense_variant	5/11	ENST00000642844.3
SLC37A4	NM_001164279.2	c.248C>T	p.Ala83Val	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC37A4	ENST00000330775.9	c.467C>T	p.Ala156Val	missense_variant	4/10	5		P1

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

GnomAD3 exomes AF: 0.00166 AC: 403 AN: 243018 Hom.: 2 AF XY: 0.00163 AC XY: 215 AN XY: 131964

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 SAS exome AF: 0.000301

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

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000589

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000245

Gnomad4 FIN exome AF: 0.00355

Gnomad4 NFE exome AF: 0.00286

Gnomad4 OTH exome AF: 0.00151

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

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00283 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:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glucose-6-phosphate transport defect Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SLC37A4: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2020	This variant is associated with the following publications: (PMID: 22899091) -

Glycogen storage disease, type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 01, 2021

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

Benign, criteria provided, single submitter

clinical testing

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

Aug 02, 2023

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
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T;T;T;T
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs201036248; hg19: chr11-118898497;