11-119027660-T-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.77

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	Protein	UniProt
SLC37A4	NM_001164278.2 link	c.593A>T	p.Asn198Ile	missense_variant	Exon 6 of 12	NP_001157750.1	O43826-2A0A024R3L1
SLC37A4	NM_001164277.2 link	c.593A>T	p.Asn198Ile	missense_variant	Exon 6 of 11	NP_001157749.1	O43826-1A0A024R3H9A8K0S7
SLC37A4	NM_001164280.2 link	c.593A>T	p.Asn198Ile	missense_variant	Exon 4 of 9	NP_001157752.1	O43826-1A0A024R3H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9 link	c.593A>T	p.Asn198Ile	missense_variant	Exon 5 of 10	5		ENSP00000476242.2		U3KPU7

Frequencies

GnomAD3 genomes

AF:

0.00388

AC:

590

AN:

152188

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00366

AC XY:

494

AN XY:

135134

show subpopulations

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.:

Cov.:

AF XY:

0.00493

AC XY:

3581

AN XY:

727092

show subpopulations

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.:

Cov.:

AF XY:

0.00369

AC XY:

275

AN XY:

74492

show subpopulations

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.:

Bravo

AF:

0.00396

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00120

AC:

ESP6500EA

AF:

0.00618

AC:

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

LINK: link

Submissions by phenotype

not provided

Benign:8

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC37A4: BS2 -

not specified

Benign:2

Oct 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glucose-6-phosphate transport defect

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.40

T;T;T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.015

T;T;T;T

PrimateAI

Uncertain

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over