rs193302892

Variant names:

• chr11-119027808-C-T
• rs193302892
• NM_001164277.2:c.446G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP3_Moderate PP5_Very_Strong

The NM_001164277.2(SLC37A4):​c.446G>A​(p.Gly149Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,457,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001376055: Experimental studies have shown that this missense change affects SLC37A4 function (PMID:10026167, 12444104)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G149G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SLC37A4 NM_001164277.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.38
• Publications: 20 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001376055: Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 10026167, 12444104).; SCV001426820: Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant almost completely abolishes the glucose-6-phosphate transport activity of the protein (e.g. Hiraiwa_1999, Chen_2002, Chen_2008).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001164277.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 11-119027808-C-T is Pathogenic according to our data. Variant chr11-119027808-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 68280.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.446G>A	p.Gly149Glu	missense	Exon 5 of 11	NP_001157749.1	O43826-1
	SLC37A4	NM_001164278.2		c.446G>A	p.Gly149Glu	missense	Exon 5 of 12	NP_001157750.1	O43826-2
	SLC37A4	NM_001164280.2		c.446G>A	p.Gly149Glu	missense	Exon 3 of 9	NP_001157752.1	O43826-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC37A4	ENST00000330775.9	TSL:5	c.446G>A	p.Gly149Glu	missense	Exon 4 of 10	ENSP00000476242.2	U3KPU7
	SLC37A4	ENST00000524428.5	TSL:1	n.767G>A		non_coding_transcript_exon	Exon 2 of 6
	SLC37A4	ENST00000525039.5	TSL:1	n.869G>A		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000292 AC: 7 AN: 239678 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1457168 Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3 AN XY: 724498

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 43798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.000278 AC: 11 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 85516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109740

Other (OTH) AF: 0.0000332 AC: 2 AN: 60232

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Glucose-6-phosphate transport defect (5)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	28
DANN	Benign	0.90
DEOGEN2	Uncertain	0.45	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.84	D
PhyloP100		7.4
PrimateAI	Pathogenic	0.85	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MVP		0.52
MPC		0.19
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs193302892; hg19: chr11-118898518;