chr11-119025270-CAG-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001164277.2(SLC37A4):c.1042_1043delCT(p.Leu348ValfsTer53) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,612,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L348L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SLC37A4
NM_001164277.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 8.71

Publications

36 publications found

Variant links:

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 links:

TRAPPC4 (HGNC:19943): (trafficking protein particle complex subunit 4) Involved in autophagy and endoplasmic reticulum to Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TRAPPC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-119025270-CAG-C is Pathogenic according to our data. Variant chr11-119025270-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 6926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC37A4	NM_001164277.2	MANE Select	c.1042_1043delCT	p.Leu348ValfsTer53	frameshift	Exon 10 of 11	NP_001157749.1	O43826-1
SLC37A4	NM_001164278.2		c.1108_1109delCT	p.Leu370ValfsTer53	frameshift	Exon 11 of 12	NP_001157750.1	O43826-2
SLC37A4	NM_001164280.2		c.1042_1043delCT	p.Leu348ValfsTer53	frameshift	Exon 8 of 9	NP_001157752.1	O43826-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC37A4	ENST00000330775.9	TSL:5	c.1042_1043delCT	p.Leu348ValfsTer53	frameshift	Exon 9 of 10	ENSP00000476242.2	U3KPU7
SLC37A4	ENST00000524428.5	TSL:1	n.1278_1279delCT		non_coding_transcript_exon	Exon 5 of 6
SLC37A4	ENST00000525039.5	TSL:1	n.1532_1533delCT		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000167

AC:

AN:

246170

AF XY:

0.000172

show subpopulations

Gnomad AFR exome

AF:

0.0000657

Gnomad AMR exome

AF:

0.000322

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000189

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000175

AC:

256

AN:

1460488

Hom.:

AF XY:

0.000182

AC XY:

132

AN XY:

726420

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33462

American (AMR)

AF:

0.000315

AC:

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26106

East Asian (EAS)

AF:

0.000101

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000193

AC:

215

AN:

1111346

Other (OTH)

AF:

0.000133

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000256

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41576

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000400

Hom.:

Bravo

AF:

0.000159

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucose-6-phosphate transport defect (11)

not provided (5)

Congenital disorder of glycosylation, type IIw (2)

Phosphate transport defect (2)

Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect (1)

Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw (1)

Glycogen storage disease (1)

Glycogen storage disease, type I (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.7

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over