ENST00000330775.9:c.345dupG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000330775.9(SLC37A4):c.345dupG(p.Leu116AlafsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000361 in 1,605,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G115G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

SLC37A4
ENST00000330775.9 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.0380

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation, type IIw
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
glycogen storage disease Ib
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
glycogen storage disease type 1 due to SLC37A4 mutation
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health

SLC37A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-119028229-G-GC is Pathogenic according to our data. Variant chr11-119028229-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 529223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
SLC37A4	NM_001164278.2 link	c.345dupG	p.Leu116AlafsTer15	frameshift_variant	Exon 4 of 12	NP_001157750.1	O43826-2A0A024R3L1
SLC37A4	NM_001164277.2 link	c.345dupG	p.Leu116AlafsTer15	frameshift_variant	Exon 4 of 11	NP_001157749.1	O43826-1A0A024R3H9A8K0S7
SLC37A4	NM_001164280.2 link	c.345dupG	p.Leu116AlafsTer15	frameshift_variant	Exon 2 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.345dupG	p.Leu116AlafsTer15	frameshift_variant	Exon 3 of 10	5		ENSP00000476242.2		U3KPU7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000855

AC:

AN:

233828

AF XY:

0.0000158

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000392

AC:

AN:

1452950

Hom.:

Cov.:

AF XY:

0.0000374

AC XY:

AN XY:

721768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33288

American (AMR)

AF:

0.00

AC:

AN:

43246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39394

South Asian (SAS)

AF:

0.00

AC:

AN:

84430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000505

AC:

AN:

1107992

Other (OTH)

AF:

0.0000166

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucose-6-phosphate transport defect

Pathogenic:2

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu116Alafs*15) in the SLC37A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC37A4 are known to be pathogenic (PMID: 9758626, 10940311). This variant is present in population databases (rs782604758, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SLC37A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 529223). For these reasons, this variant has been classified as Pathogenic. -

Jan 17, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.038

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over