rs34203644

Positions:

• chr11-119027660-T-A
• chr11-119027660-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (23 hom.)
• Consequence: SLC37A4 NM_001164278.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.77

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.593A>T	p.Asn198Ile	missense_variant	6/12		NP_001157750.1
SLC37A4	NM_001164277.2	c.593A>T	p.Asn198Ile	missense_variant	6/11		NP_001157749.1
SLC37A4	NM_001164280.2	c.593A>T	p.Asn198Ile	missense_variant	4/9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.593A>T	p.Asn198Ile	missense_variant	5/10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 590 AN: 152188 Hom.: 4 Cov.: 33

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

GnomAD3 exomes AF: 0.00363 AC: 903 AN: 249060 Hom.: 4 AF XY: 0.00366 AC XY: 494 AN XY: 135134

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00523

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00595

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.00387 AC: 590 AN: 152306 Hom.: 4 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74492

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.00473

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

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 19, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC37A4: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -

Glucose-6-phosphate transport defect Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -

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

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

Other links and lift over

dbSNP: rs34203644; hg19: chr11-118898370;