chr11-119028193-C-A

Variant names:

• chr11-119028193-C-A
• rs786204637
• NM_001164277.2:c.381+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001164277.2(SLC37A4):​c.381+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,426,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SLC37A4 NM_001164277.2 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• glycogen storage disease Ib

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• glycogen storage disease type 1 due to SLC37A4 mutation

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 11-119028193-C-A is Pathogenic according to our data. Variant chr11-119028193-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 656028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164277.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC37A4	NM_001164277.2	MANE Select	c.381+1G>T		splice_donor intron	N/A	NP_001157749.1	O43826-1
	SLC37A4	NM_001164278.2		c.381+1G>T		splice_donor intron	N/A	NP_001157750.1	O43826-2
	SLC37A4	NM_001164280.2		c.381+1G>T		splice_donor intron	N/A	NP_001157752.1	O43826-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC37A4	ENST00000330775.9	TSL:5	c.381+1G>T		splice_donor intron	N/A	ENSP00000476242.2	U3KPU7
	SLC37A4	ENST00000524428.5	TSL:1	n.382G>T		non_coding_transcript_exon	Exon 2 of 6
	SLC37A4	ENST00000526275.5	TSL:1	n.842G>T		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000126 AC: 18 AN: 1426580 Hom.: 0 Cov.: 30 AF XY: 0.0000156 AC XY: 11 AN XY: 707172

African (AFR) AF: 0.0000307 AC: 1 AN: 32584

American (AMR) AF: 0.00 AC: 0 AN: 39846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25510

East Asian (EAS) AF: 0.00 AC: 0 AN: 38204

South Asian (SAS) AF: 0.00 AC: 0 AN: 81862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000156 AC: 17 AN: 1092442

Other (OTH) AF: 0.00 AC: 0 AN: 59212

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Glucose-6-phosphate transport defect (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		7.3
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204637; hg19: chr11-118898903;