rs759458

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003038.5(SLC1A4):c.1195G>A(p.Val399Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,613,822 control chromosomes in the GnomAD database, including 51,425 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V399V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 3936 hom., cov: 32)

Exomes 𝑓: 0.25 ( 47489 hom. )

Consequence

SLC1A4
NM_003038.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.526

Publications

49 publications found

Variant links:

Genes affected

SLC1A4 (HGNC:10942): (solute carrier family 1 member 4) The protein encoded by this gene is a sodium-dependent neutral amino acid transporter for alanine, serine, cysteine, and threonine. Defects in this gene have been associated with developmental delay, microcephaly, and intellectual disability. [provided by RefSeq, Jan 2017]

SLC1A4 links:

LINC02245 (HGNC:53134): (long intergenic non-protein coding RNA 2245)

LINC02245 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019662976).

BP6

Variant 2-65018231-G-A is Benign according to our data. Variant chr2-65018231-G-A is described in ClinVar as Benign. ClinVar VariationId is 1167921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC1A4	NM_003038.5 link	c.1195G>A	p.Val399Ile	missense_variant	Exon 6 of 8	ENST00000234256.4	NP_003029.2
SLC1A4	NM_001348406.2 link	c.535G>A	p.Val179Ile	missense_variant	Exon 6 of 8		NP_001335335.1
SLC1A4	NM_001348407.2 link	c.535G>A	p.Val179Ile	missense_variant	Exon 6 of 8		NP_001335336.1
SLC1A4	NM_001193493.2 link	c.301G>A	p.Val101Ile	missense_variant	Exon 5 of 7		NP_001180422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A4	ENST00000234256.4 link	c.1195G>A	p.Val399Ile	missense_variant	Exon 6 of 8	1	NM_003038.5	ENSP00000234256.3

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33569

AN:

151964

Hom.:

3938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.335

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.302

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.249

GnomAD2 exomes

AF:

0.235

AC:

58965

AN:

251332

AF XY:

0.247

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.143

Gnomad ASJ exome

AF:

0.341

Gnomad EAS exome

AF:

0.130

Gnomad FIN exome

AF:

0.230

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.251

AC:

367174

AN:

1461740

Hom.:

47489

Cov.:

AF XY:

0.254

AC XY:

184843

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.167

AC:

5604

AN:

33478

American (AMR)

AF:

0.149

AC:

6658

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

9013

AN:

26134

East Asian (EAS)

AF:

0.131

AC:

5197

AN:

39698

South Asian (SAS)

AF:

0.315

AC:

27157

AN:

86256

European-Finnish (FIN)

AF:

0.230

AC:

12275

AN:

53420

Middle Eastern (MID)

AF:

0.375

AC:

2162

AN:

5768

European-Non Finnish (NFE)

AF:

0.255

AC:

283147

AN:

1111880

Other (OTH)

AF:

0.264

AC:

15961

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

14971

29942

44912

59883

74854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9514

19028

28542

38056

47570

<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:

0.221

AC:

33573

AN:

152082

Hom.:

3936

Cov.:

AF XY:

0.218

AC XY:

16171

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.164

AC:

6808

AN:

41490

American (AMR)

AF:

0.193

AC:

2941

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

1163

AN:

3472

East Asian (EAS)

AF:

0.130

AC:

672

AN:

5184

South Asian (SAS)

AF:

0.302

AC:

1450

AN:

4806

European-Finnish (FIN)

AF:

0.235

AC:

2481

AN:

10552

Middle Eastern (MID)

AF:

0.391

AC:

115

AN:

294

European-Non Finnish (NFE)

AF:

0.254

AC:

17278

AN:

67990

Other (OTH)

AF:

0.248

AC:

523

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1346

2692

4037

5383

6729

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.250

Hom.:

16240

Bravo

AF:

0.213

TwinsUK

AF:

0.244

AC:

905

ALSPAC

AF:

0.256

AC:

986

ESP6500AA

AF:

0.175

AC:

772

ESP6500EA

AF:

0.262

AC:

2257

ExAC

AF:

0.240

AC:

29147

Asia WGS

AF:

0.254

AC:

883

AN:

3478

EpiCase

AF:

0.274

EpiControl

AF:

0.272

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.7

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.17

.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.48

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.045

.;N

PhyloP100

0.53

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.23

N;N

REVEL

Benign

0.045

Sift

Benign

0.39

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.0020

.;B

Vest4

0.037

MPC

0.26

ClinPred

0.0011

GERP RS

0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.56

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over