chr11-119027757-C-T

Variant names:

• chr11-119027757-C-T
• rs186476316
• NM_001164277.2:c.497G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001164277.2(SLC37A4):​c.497G>A​(p.Arg166His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,612,922 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R166C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: SLC37A4 NM_001164277.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:4
• Conservation: PhyloP100: 7.38
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09724784).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000906 (138/152358) while in subpopulation AFR AF = 0.00291 (121/41584). AF 95% confidence interval is 0.00249. There are 1 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.497G>A	p.Arg166His	missense	Exon 5 of 11	NP_001157749.1	O43826-1
	SLC37A4	NM_001164278.2		c.497G>A	p.Arg166His	missense	Exon 5 of 12	NP_001157750.1	O43826-2
	SLC37A4	NM_001164280.2		c.497G>A	p.Arg166His	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.497G>A	p.Arg166His	missense	Exon 4 of 10	ENSP00000476242.2	U3KPU7
	SLC37A4	ENST00000524428.5	TSL:1	n.818G>A		non_coding_transcript_exon	Exon 2 of 6
	SLC37A4	ENST00000525039.5	TSL:1	n.920G>A		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes AF: 0.000906 AC: 138 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000510 AC: 126 AN: 246818 AF XY: 0.000485

Gnomad AFR exome AF: 0.00321

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1460564 Hom.: 3 Cov.: 34 AF XY: 0.000206 AC XY: 150 AN XY: 726454

African (AFR) AF: 0.00296 AC: 99 AN: 33470

American (AMR) AF: 0.0000449 AC: 2 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000454 AC: 18 AN: 39668

South Asian (SAS) AF: 0.00164 AC: 141 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111248

Other (OTH) AF: 0.000348 AC: 21 AN: 60340

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74514

African (AFR) AF: 0.00291 AC: 121 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00387 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000579 AC: 70

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

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 (1)
-	1	-	Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw (1)
-	-	1	not specified (1)
-	-	1	SLC37A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	26
DANN	Benign	0.89
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.097	T
PhyloP100		7.4
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.0040	D
Vest4		0.91
MVP		0.46
MPC		0.22
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.78
Mutation Taster		=82/18	disease causing (ClinVar)

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: rs186476316; hg19: chr11-118898467;