ENST00000330775.9:c.1123+1G>A

Variant names:

• chr11-119025190-C-T
• rs782630676
• ENST00000330775.9:c.1123+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000330775.9(SLC37A4):​c.1123+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC37A4 ENST00000330775.9 splice_donor, intron
• Scores: Splicing: ADA: 0.9926
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.34
• 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]

TRAPPC4 (HGNC:19943): (trafficking protein particle complex subunit 4) Involved in autophagy and endoplasmic reticulum to Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119025190-C-T is Pathogenic according to our data. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-119025190-C-T is described in CliVar as Pathogenic. Clinvar id is 2678960.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.1189+1G>A		splice_donor_variant, intron_variant	Intron 11 of 11		NP_001157750.1
SLC37A4	NM_001164277.2	c.1123+1G>A		splice_donor_variant, intron_variant	Intron 10 of 10		NP_001157749.1
SLC37A4	NM_001164280.2	c.1123+1G>A		splice_donor_variant, intron_variant	Intron 8 of 8		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.1123+1G>A		splice_donor_variant, intron_variant	Intron 9 of 9	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:1

Mar 01, 2023

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
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.3
GERP RS		5.3
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 1

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

Other links and lift over

dbSNP: rs782630676; hg19: chr11-118895900;