ENST00000330775.9:c.1062C>T

Variant names:

• chr11-119025252-G-A
• rs61730035
• ENST00000330775.9:c.1062C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000330775.9(SLC37A4):​c.1062C>T​(p.Asn354Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,168 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (135 hom.)
• Consequence: SLC37A4 ENST00000330775.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.310

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-119025252-G-A is Benign according to our data. Variant chr11-119025252-G-A is described in ClinVar as [Benign]. Clinvar id is 139191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119025252-G-A is described in Lovd as [Likely_benign]. Variant chr11-119025252-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00927 (1412/152372) while in subpopulation AMR AF= 0.016 (245/15308). AF 95% confidence interval is 0.0144. There are 10 homozygotes in gnomad4. There are 659 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.1128C>T	p.Asn376Asn	synonymous_variant	Exon 11 of 12		NP_001157750.1
SLC37A4	NM_001164277.2	c.1062C>T	p.Asn354Asn	synonymous_variant	Exon 10 of 11		NP_001157749.1
SLC37A4	NM_001164280.2	c.1062C>T	p.Asn354Asn	synonymous_variant	Exon 8 of 9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.1062C>T	p.Asn354Asn	synonymous_variant	Exon 9 of 10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes AF: 0.00927 AC: 1412 AN: 152254 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00928 AC: 2291 AN: 246964 Hom.: 21 AF XY: 0.00979 AC XY: 1311 AN XY: 133976

Gnomad AFR exome AF: 0.00255

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00240

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0116 AC: 16940 AN: 1460796 Hom.: 135 Cov.: 34 AF XY: 0.0115 AC XY: 8326 AN XY: 726618

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00927 AC: 1412 AN: 152372 Hom.: 10 Cov.: 33 AF XY: 0.00884 AC XY: 659 AN XY: 74508

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0130 Hom.: 31

Bravo AF: 0.00966

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 19, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: The c.1062C>T (p.Asn354=) causes a synonymous change that involves a non-conserved nucleotide. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1.0% including numerous homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in SLC37A4 gene (0.12%). The variant has been reported as a Polymorphism/Benign in literature (Zappu, 2010) and a clinical laboratory. Taken together, the variant has been classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC37A4: BP4, BP7, BS1, BS2 -

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Glucose-6-phosphate transport defect Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Phosphate transport defect Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs61730035; hg19: chr11-118895962; COSMIC: COSV58155288; COSMIC: COSV58155288;