rs193302899

Positions:

• chr11-119028321-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate

The NM_001164278.2(SLC37A4):​c.254T>C​(p.Leu85Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC37A4 NM_001164278.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.42

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_001164278.2 (SLC37A4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical (size 20) in uniprot entity G6PT1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001164278.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.254T>C	p.Leu85Pro	missense_variant	4/12		NP_001157750.1
SLC37A4	NM_001164277.2	c.254T>C	p.Leu85Pro	missense_variant	4/11		NP_001157749.1
SLC37A4	NM_001164280.2	c.254T>C	p.Leu85Pro	missense_variant	2/9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.254T>C	p.Leu85Pro	missense_variant	3/10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Benign	0.84
DEOGEN2	Uncertain	0.57	D;D;D;D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.86	D;D;D;D
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.015	D;D;D;D
Vest4		0.87
MVP		0.50
MPC		0.21
GERP RS		5.2
gMVP		0.94

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: rs193302899; hg19: chr11-118899031;