dbSNP rs59638403: SLC19A1:p.Leu338Phe (chr21-45530909-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_194255.4(SLC19A1):c.1012C>T(p.Leu338Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,476,568 control chromosomes in the GnomAD database, including 15 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 (★★).

Frequency

Genomes: 𝑓 0.0041 ( 8 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 7 hom. )

Consequence

SLC19A1
NM_194255.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.81

Publications

6 publications found

Variant links:

Genes affected

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

SLC19A1 Gene-Disease associations (from GenCC):

combined immunodeficiency
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
immunodeficiency 114, folate-responsive
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
megaloblastic anemia, folate-responsive
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

SLC19A1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_194255.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.011762321).

BP6

Variant 21-45530909-G-A is Benign according to our data. Variant chr21-45530909-G-A is described in ClinVar as Benign. ClinVar VariationId is 724746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00041 (543/1325796) while in subpopulation AFR AF = 0.0168 (445/26528). AF 95% confidence interval is 0.0155. There are 7 homozygotes in GnomAdExome4. There are 233 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A1	NM_194255.4	MANE Select	c.1012C>T	p.Leu338Phe	missense	Exon 4 of 6	NP_919231.1	P41440-1
SLC19A1	NM_001352512.2		c.1012C>T	p.Leu338Phe	missense	Exon 4 of 6	NP_001339441.1	P41440-1
SLC19A1	NM_001205207.3		c.892C>T	p.Leu298Phe	missense	Exon 3 of 5	NP_001192136.1	P41440-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.1012C>T	p.Leu338Phe	missense	Exon 4 of 6	ENSP00000308895.4	P41440-1
SLC19A1	ENST00000567670.5	TSL:1	c.1012C>T	p.Leu338Phe	missense	Exon 4 of 6	ENSP00000457278.1	H3BTQ3
SLC19A1	ENST00000380010.8	TSL:1	c.1012C>T	p.Leu338Phe	missense	Exon 4 of 6	ENSP00000369347.4	P41440-3

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

620

AN:

150650

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000420

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.000970

GnomAD2 exomes

AF:

0.00124

AC:

162

AN:

130798

AF XY:

0.000868

show subpopulations

Gnomad AFR exome

AF:

0.0156

Gnomad AMR exome

AF:

0.000563

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000461

Gnomad OTH exome

AF:

0.000371

GnomAD4 exome

AF:

0.000410

AC:

543

AN:

1325796

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

233

AN XY:

648568

show subpopulations

African (AFR)

AF:

0.0168

AC:

445

AN:

26528

American (AMR)

AF:

0.000485

AC:

AN:

24736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18804

East Asian (EAS)

AF:

0.00

AC:

AN:

33106

South Asian (SAS)

AF:

0.0000443

AC:

AN:

67740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46822

Middle Eastern (MID)

AF:

0.000768

AC:

AN:

5208

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

1048618

Other (OTH)

AF:

0.000867

AC:

AN:

54234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00411

AC:

620

AN:

150772

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

306

AN XY:

73648

show subpopulations

African (AFR)

AF:

0.0143

AC:

586

AN:

41060

American (AMR)

AF:

0.00184

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4928

South Asian (SAS)

AF:

0.000210

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67500

Other (OTH)

AF:

0.000960

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00375

Hom.:

Bravo

AF:

0.00484

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

SLC19A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.25

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

PhyloP100

1.8

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

REVEL

Benign

0.20

Sift

Benign

0.090

Sift4G

Uncertain

0.019

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.66

Mutation Taster

=75/25

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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