Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001164277.2(SLC37A4):c.1224G>A(p.Thr408Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,613,786 control chromosomes in the GnomAD database, including 42,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5112 hom., cov: 33)

Exomes 𝑓: 0.22 ( 37150 hom. )

Consequence

SLC37A4
NM_001164277.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -1.13

Publications

33 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030011535).

BP6

Variant 11-119024976-C-T is Benign according to our data. Variant chr11-119024976-C-T is described in ClinVar as Benign. ClinVar VariationId is 139192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

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
SLC37A4	NM_001164277.2	MANE Select	c.1224G>A	p.Thr408Thr	synonymous	Exon 11 of 11	NP_001157749.1
SLC37A4	NM_001164278.2		c.1290G>A	p.Thr430Thr	synonymous	Exon 12 of 12	NP_001157750.1
SLC37A4	NM_001164280.2		c.1224G>A	p.Thr408Thr	synonymous	Exon 9 of 9	NP_001157752.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC37A4	ENST00000330775.9	TSL:5	c.1224G>A	p.Thr408Thr	synonymous	Exon 10 of 10	ENSP00000476242.2
SLC37A4	ENST00000524428.5	TSL:1	n.1460G>A		non_coding_transcript_exon	Exon 6 of 6
SLC37A4	ENST00000525039.5	TSL:1	n.1714G>A		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes

AF:

0.248

AC:

37675

AN:

152096

Hom.:

5085

Cov.:

show subpopulations

Gnomad AFR

AF:

0.347

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.0891

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.246

GnomAD2 exomes

AF:

0.214

AC:

53158

AN:

248950

AF XY:

0.220

show subpopulations

Gnomad AFR exome

AF:

0.356

Gnomad AMR exome

AF:

0.149

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.0901

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.222

AC:

324203

AN:

1461572

Hom.:

37150

Cov.:

AF XY:

0.224

AC XY:

162849

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.355

AC:

11876

AN:

33478

American (AMR)

AF:

0.158

AC:

7070

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

4935

AN:

26136

East Asian (EAS)

AF:

0.114

AC:

4518

AN:

39678

South Asian (SAS)

AF:

0.292

AC:

25229

AN:

86254

European-Finnish (FIN)

AF:

0.221

AC:

11825

AN:

53394

Middle Eastern (MID)

AF:

0.245

AC:

1415

AN:

5768

European-Non Finnish (NFE)

AF:

0.219

AC:

243340

AN:

1111780

Other (OTH)

AF:

0.232

AC:

13995

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15360

30719

46079

61438

76798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8588

17176

25764

34352

42940

<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:

0.248

AC:

37746

AN:

152214

Hom.:

5112

Cov.:

AF XY:

0.248

AC XY:

18424

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.348

AC:

14439

AN:

41508

American (AMR)

AF:

0.209

AC:

3202

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

596

AN:

3470

East Asian (EAS)

AF:

0.0893

AC:

463

AN:

5184

South Asian (SAS)

AF:

0.305

AC:

1473

AN:

4828

European-Finnish (FIN)

AF:

0.231

AC:

2446

AN:

10602

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.212

AC:

14400

AN:

68018

Other (OTH)

AF:

0.249

AC:

526

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1466

2933

4399

5866

7332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.222

Hom.:

9510

Bravo

AF:

0.247

TwinsUK

AF:

0.216

AC:

800

ALSPAC

AF:

0.216

AC:

834

ESP6500AA

AF:

0.337

AC:

1363

ESP6500EA

AF:

0.216

AC:

1809

ExAC

AF:

0.218

AC:

26367

Asia WGS

AF:

0.233

AC:

813

AN:

3478

EpiCase

AF:

0.212

EpiControl

AF:

0.220

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucose-6-phosphate transport defect (3)

not specified (2)

not provided (2)

Phosphate transport defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.6

(source)

DANN

Benign

0.85

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.14

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.98

PhyloP100

-1.1

PROVEAN

Benign

0.040

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Vest4

0.093

ClinPred

0.016

GERP RS

-0.051

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over