11-119026079-G-C

Variant names:

• chr11-119026079-G-C
• rs200147602
• NM_001164277.2:c.872C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The ENST00000330775.9(SLC37A4):​c.872C>G​(p.Ala291Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,586,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A291V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.79
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)
• glycogen storage disease Ib

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019008964).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000606 (87/1434508) while in subpopulation AFR AF = 0.00185 (61/32930). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAdExome4. There are 40 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000330775.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC37A4	NM_001164277.2	MANE Select	c.872C>G	p.Ala291Gly	missense splice_region	Exon 9 of 11	NP_001157749.1
	SLC37A4	NM_001164278.2		c.872C>G	p.Ala291Gly	missense splice_region	Exon 9 of 12	NP_001157750.1
	SLC37A4	NM_001164280.2		c.872C>G	p.Ala291Gly	missense splice_region	Exon 7 of 9	NP_001157752.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC37A4	ENST00000330775.9	TSL:5	c.872C>G	p.Ala291Gly	missense splice_region	Exon 8 of 10	ENSP00000476242.2
	SLC37A4	ENST00000524428.5	TSL:1	n.1108C>G		splice_region non_coding_transcript_exon	Exon 4 of 6
	SLC37A4	ENST00000525039.5	TSL:1	n.1296C>G		splice_region non_coding_transcript_exon	Exon 8 of 11

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000192 AC: 40 AN: 208402 AF XY: 0.000197

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000654

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.0000606 AC: 87 AN: 1434508 Hom.: 0 Cov.: 30 AF XY: 0.0000562 AC XY: 40 AN XY: 711284

African (AFR) AF: 0.00185 AC: 61 AN: 32930

American (AMR) AF: 0.000271 AC: 11 AN: 40562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25528

East Asian (EAS) AF: 0.00 AC: 0 AN: 38412

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000820 AC: 9 AN: 1097724

Other (OTH) AF: 0.0000841 AC: 5 AN: 59456

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74436

African (AFR) AF: 0.00173 AC: 72 AN: 41532

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00000755 Hom.: 0

Bravo AF: 0.000620

ExAC AF: 0.000199 AC: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Glucose-6-phosphate transport defect (2)
-	1	1	not provided (2)
-	1	-	Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	SLC37A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.62
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.019	T
PhyloP100		1.8
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.42	T
Vest4		0.33
MVP		0.57
MPC		0.034
GERP RS		3.5
gMVP		0.18
Mutation Taster		=84/16	polymorphism

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: rs200147602; hg19: chr11-118896789;