rs201036248

Variant names:

• chr11-119027787-G-A
• rs201036248
• NM_001164277.2:c.467C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001164277.2(SLC37A4):​c.467C>T​(p.Ala156Val) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,611,414 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A156A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: SLC37A4 NM_001164277.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 5.24
• Publications: 3 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001164277.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011417329).
• BP6: Variant 11-119027787-G-A is Benign according to our data. Variant chr11-119027787-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215177.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00205 (312/152362) while in subpopulation NFE AF = 0.00341 (232/68040). AF 95% confidence interval is 0.00305. There are 1 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

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.467C>T	p.Ala156Val	missense	Exon 5 of 11	NP_001157749.1	O43826-1
	SLC37A4	NM_001164278.2		c.467C>T	p.Ala156Val	missense	Exon 5 of 12	NP_001157750.1	O43826-2
	SLC37A4	NM_001164280.2		c.467C>T	p.Ala156Val	missense	Exon 3 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.467C>T	p.Ala156Val	missense	Exon 4 of 10	ENSP00000476242.2	U3KPU7
	SLC37A4	ENST00000524428.5	TSL:1	n.788C>T		non_coding_transcript_exon	Exon 2 of 6
	SLC37A4	ENST00000525039.5	TSL:1	n.890C>T		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 312 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00166 AC: 403 AN: 243018 AF XY: 0.00163

Gnomad AFR exome AF: 0.000268

Gnomad AMR exome AF: 0.000773

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.00241 AC: 3514 AN: 1459052 Hom.: 9 Cov.: 34 AF XY: 0.00240 AC XY: 1744 AN XY: 725606

African (AFR) AF: 0.000239 AC: 8 AN: 33444

American (AMR) AF: 0.000589 AC: 26 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26078

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.000245 AC: 21 AN: 85830

European-Finnish (FIN) AF: 0.00355 AC: 189 AN: 53226

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00286 AC: 3171 AN: 1110648

Other (OTH) AF: 0.00151 AC: 91 AN: 60282

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00209 AC XY: 156 AN XY: 74504

African (AFR) AF: 0.000289 AC: 12 AN: 41590

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68040

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00155 AC: 13

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Glucose-6-phosphate transport defect (2)
-	1	-	Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect (1)
-	1	-	Glycogen storage disease, type I (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.81
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T
PhyloP100		5.2
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.64	T
Vest4		0.42
MVP		0.33
MPC		0.027
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.87
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs201036248; hg19: chr11-118898497;