chr11-119026079-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001164277.2(SLC37A4):​c.872C>T​(p.Ala291Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,586,760 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. A291G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: SLC37A4 NM_001164277.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008605182).
• BP6: Variant 11-119026079-G-A is Benign according to our data. Variant chr11-119026079-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459625.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (187/152254) while in subpopulation AFR AF = 0.00424 (176/41532). AF 95% confidence interval is 0.00373. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC37A4	NM_001164277.2	MANE Select	c.872C>T	p.Ala291Val	missense splice_region	Exon 9 of 11	NP_001157749.1
	SLC37A4	NM_001164278.2		c.872C>T	p.Ala291Val	missense splice_region	Exon 9 of 12	NP_001157750.1
	SLC37A4	NM_001164280.2		c.872C>T	p.Ala291Val	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>T	p.Ala291Val	missense splice_region	Exon 8 of 10	ENSP00000476242.2
	SLC37A4	ENST00000524428.5	TSL:1	n.1108C>T		splice_region non_coding_transcript_exon	Exon 4 of 6
	SLC37A4	ENST00000525039.5	TSL:1	n.1296C>T		splice_region non_coding_transcript_exon	Exon 8 of 11

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000341 AC: 71 AN: 208402 AF XY: 0.000313

Gnomad AFR exome AF: 0.00467

Gnomad AMR exome AF: 0.000237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000327

Gnomad OTH exome AF: 0.000376

GnomAD4 exome AF: 0.000192 AC: 276 AN: 1434506 Hom.: 0 Cov.: 30 AF XY: 0.000172 AC XY: 122 AN XY: 711284

African (AFR) AF: 0.00577 AC: 190 AN: 32928

American (AMR) AF: 0.000320 AC: 13 AN: 40562

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

East Asian (EAS) AF: 0.0000521 AC: 2 AN: 38412

South Asian (SAS) AF: 0.0000364 AC: 3 AN: 82364

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

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5726

European-Non Finnish (NFE) AF: 0.0000310 AC: 34 AN: 1097724

Other (OTH) AF: 0.000505 AC: 30 AN: 59456

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74436

African (AFR) AF: 0.00424 AC: 176 AN: 41532

American (AMR) AF: 0.000261 AC: 4 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: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.00150

ESP6500AA AF: 0.00288 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000356 AC: 43

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Glucose-6-phosphate transport defect (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SLC37A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.63
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0086	T
PhyloP100		1.8
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.45	T
Vest4		0.18
MVP		0.53
MPC		0.026
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20
Mutation Taster		=81/19	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;