Genetic Variant NM_194255.4:c.1406C>T (chr21-45516028-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.1406C>T(p.Ala469Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,578,286 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A469S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 34)

Exomes 𝑓: 0.0021 ( 39 hom. )

Consequence

SLC19A1
NM_194255.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.144

Publications

10 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

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0028970242).

BP6

Variant 21-45516028-G-A is Benign according to our data. Variant chr21-45516028-G-A is described in ClinVar as Benign. ClinVar VariationId is 1652889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1619/152320) while in subpopulation AFR AF = 0.0336 (1396/41568). AF 95% confidence interval is 0.0321. There are 24 homozygotes in GnomAd4. There are 761 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 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.1406C>T	p.Ala469Val	missense	Exon 6 of 6	NP_919231.1	P41440-1
SLC19A1	NM_001352512.2		c.1406C>T	p.Ala469Val	missense	Exon 6 of 6	NP_001339441.1	P41440-1
SLC19A1	NM_001205207.3		c.1286C>T	p.Ala429Val	missense	Exon 5 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.1406C>T	p.Ala469Val	missense	Exon 6 of 6	ENSP00000308895.4	P41440-1
SLC19A1	ENST00000567670.5	TSL:1	c.1293+9789C>T		intron	N/A	ENSP00000457278.1	H3BTQ3
SLC19A1	ENST00000380010.8	TSL:1	c.1294-876C>T		intron	N/A	ENSP00000369347.4	P41440-3

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1615

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00446

AC:

824

AN:

184868

AF XY:

0.00450

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.000589

Gnomad EAS exome

AF:

0.000423

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000778

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00211

AC:

3006

AN:

1425966

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1617

AN XY:

705972

show subpopulations

African (AFR)

AF:

0.0353

AC:

1170

AN:

33164

American (AMR)

AF:

0.00372

AC:

140

AN:

37660

Ashkenazi Jewish (ASJ)

AF:

0.000318

AC:

AN:

25194

East Asian (EAS)

AF:

0.000155

AC:

AN:

38612

South Asian (SAS)

AF:

0.0115

AC:

941

AN:

81974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49176

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000381

AC:

417

AN:

1095320

Other (OTH)

AF:

0.00399

AC:

236

AN:

59162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0106

AC:

1619

AN:

152320

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

761

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0336

AC:

1396

AN:

41568

American (AMR)

AF:

0.00594

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.0116

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68018

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00247

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0276

AC:

118

ESP6500EA

AF:

0.000603

AC:

ExAC

AF:

0.00443

AC:

519

Asia WGS

AF:

0.00808

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.14

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

REVEL

Benign

0.054

Sift

Benign

0.092

Sift4G

Uncertain

0.054

Polyphen

0.13

Vest4

0.019

MVP

0.26

MPC

0.13

ClinPred

0.0092

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.28

Mutation Taster

=98/2

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

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