rs186143284

Variant names:

Variant summary

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

The NM_080669.6(SLC46A1):c.1366C>T(p.Pro456Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,990 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P456L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 15 hom. )

Consequence

SLC46A1
NM_080669.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.286

Publications

9 publications found

Variant links:

Genes affected

SLC46A1 (HGNC:30521): (solute carrier family 46 member 1) This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

SLC46A1 links:

SARM1 (HGNC:17074): (sterile alpha and TIR motif containing 1) Enables NAD+ nucleotidase, cyclic ADP-ribose generating and identical protein binding activity. Involved in NAD catabolic process; positive regulation of neuron death; and response to axon injury. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SARM1 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=0.003211528).

BP6

Variant 17-28399670-G-A is Benign according to our data. Variant chr17-28399670-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00226 (344/152296) while in subpopulation NFE AF = 0.00356 (242/68032). AF 95% confidence interval is 0.00319. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC46A1	NM_080669.6 link	c.1366C>T	p.Pro456Ser	missense_variant	Exon 5 of 5	ENST00000612814.5	NP_542400.2
SARM1	NM_015077.4 link	c.*3384G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000585482.6	NP_055892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC46A1	ENST00000612814.5 link	c.1366C>T	p.Pro456Ser	missense_variant	Exon 5 of 5	2	NM_080669.6	ENSP00000480703.1
SLC46A1	ENST00000618626.1 link	c.1282C>T	p.Pro428Ser	missense_variant	Exon 4 of 4	1		ENSP00000483652.1
SARM1	ENST00000585482.6 link	c.*3384G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_015077.4	ENSP00000468032.2
SLC46A1	ENST00000582735.1 link	c.249C>T	p.Phe83Phe	synonymous_variant	Exon 2 of 2	4		ENSP00000463339.1

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

344

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00356

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00311

AC:

770

AN:

247576

AF XY:

0.00301

show subpopulations

Gnomad AFR exome

AF:

0.000581

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00654

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00330

AC:

4819

AN:

1461694

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

2316

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.000313

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000638

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00698

AC:

373

AN:

53402

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00374

AC:

4161

AN:

1111856

Other (OTH)

AF:

0.00258

AC:

156

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

244

487

731

974

1218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00226

AC:

344

AN:

152296

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41562

American (AMR)

AF:

0.000392

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00566

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00356

AC:

242

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00351

Hom.:

Bravo

AF:

0.00205

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00444

AC:

ExAC

AF:

0.00346

AC:

418

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SARM1: BS2; SLC46A1: BP4, BS2

Apr 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Sep 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC46A1 c.1366C>T (p.Pro456Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 247576 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC46A1 causing Congenital Defect Of Folate Absorption phenotype (0.0011). c.1366C>T has been reported in the literature in individuals affected with intellectual disability and individuals from general population in a case-control study for factors affecting Folate levels (Pavlkova_2012, Redin_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Defect Of Folate Absorption. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22695967, 25167861). ClinVar contains an entry for this variant (Variation ID: 235433). Based on the evidence outlined above, the variant was classified as likely benign.

Nov 03, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC46A1-related disorder

Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.

PhyloP100

0.29

PrimateAI

Benign

0.31

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Benign

0.85

T;T

Vest4

0.047

ClinPred

0.0029

GERP RS

0.37

Varity_R

0.028

gMVP

0.31

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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