chr11-119027012-ACAC-A

Variant names:

• chr11-119027012-ACAC-A
• rs121908977
• NM_001164277.2:c.706_708delGTG

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM4_Supporting PP5_Very_Strong

The NM_001164277.2(SLC37A4):​c.706_708delGTG​(p.Val236del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001392637: Experimental studies have shown that this variant affects SLC37A4 function (PMID:12444104).". Synonymous variant affecting the same amino acid position (i.e. V236V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC37A4 NM_001164277.2 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.73
• Publications: 5 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001392637: Experimental studies have shown that this variant affects SLC37A4 function (PMID: 12444104).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001164277.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-119027012-ACAC-A is Pathogenic according to our data. Variant chr11-119027012-ACAC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6930.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.706_708delGTG	p.Val236del	conservative_inframe_deletion	Exon 7 of 11	NP_001157749.1	O43826-1
	SLC37A4	NM_001164278.2		c.706_708delGTG	p.Val236del	conservative_inframe_deletion	Exon 7 of 12	NP_001157750.1	O43826-2
	SLC37A4	NM_001164280.2		c.706_708delGTG	p.Val236del	conservative_inframe_deletion	Exon 5 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.706_708delGTG	p.Val236del	conservative_inframe_deletion	Exon 6 of 10	ENSP00000476242.2	U3KPU7
	SLC37A4	ENST00000524428.5	TSL:1	n.1028_1030delGTG		non_coding_transcript_exon	Exon 3 of 6
	SLC37A4	ENST00000525039.5	TSL:1	n.1130_1132delGTG		non_coding_transcript_exon	Exon 6 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461562 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727058

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Glucose-6-phosphate transport defect (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs121908977; hg19: chr11-118897722;