11-119027757-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000330775.9(SLC37A4):c.497G>A(p.Arg166His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,612,922 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign 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. R166C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 3 hom. )

Consequence

SLC37A4
ENST00000330775.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: 7.38

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09724784).

BS2

High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC37A4	NM_001164277.2 linkuse as main transcript	c.497G>A	p.Arg166His	missense_variant	5/11	ENST00000642844.3
SLC37A4	NM_001164279.2 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC37A4	ENST00000330775.9 linkuse as main transcript	c.497G>A	p.Arg166His	missense_variant	4/10	5		P1

Frequencies

GnomAD3 genomes

AF:

0.000906

AC:

138

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000510

AC:

126

AN:

246818

Hom.:

AF XY:

0.000485

AC XY:

AN XY:

133952

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.0000585

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00224

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.000502

GnomAD4 exome

AF:

0.000211

AC:

308

AN:

1460564

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

150

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000454

Gnomad4 SAS exome

AF:

0.00164

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152358

Hom.:

Cov.:

AF XY:

0.000966

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00387

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000579

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2015	p.Arg166His (CGC>CAC): c.497 G>A in exon 5 of the SLC37A4 gene (NM_001164277.1) The R166H variant in the SLC37A4 gene is likely pathogenic. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Mutations in the SLC37A4 gene are associated with the autosomal recessive disorders glycogen storage disease Ib and Ic The R166H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is highly conserved across species. A non-conservative missense change at the same position (R166L) has been reported previously in association with glycogen storage disease Ib (Chen et al., 2008). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (A156V, C176R) have also been reported in association with glycogen storage disease Ib, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in LAPDH-MITOP,MITONUC-MITOP panel(s). -

Glucose-6-phosphate transport defect

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2020	- -

Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

SLC37A4 NM_001164277.1 exon 5 p.Arg166His (c.497G>A): This variant has not been reported in the literature but is present in 0.3% (73/23994) of African alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/11-118898467-C-T). This variant is present in ClinVar (Variation ID:215178). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, another variant at this residue (p.Arg166Leu) has been reported in association with disease (Glycogen storage disease 1B) (Kojima 2004 PMID:15059622, Chen 2008 PMID:18835800). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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

Jun 20, 2019

SLC37A4-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Benign

0.89

DEOGEN2

Uncertain

0.46

T;T;T;T

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.097

T;T;T;T

PrimateAI

Uncertain

0.55

Sift4G

Uncertain

0.0040

D;D;D;D

Vest4

0.91

MVP

0.46

MPC

0.22

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.78

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

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