rs186143284

Positions:

chr17-28399670-G-A

Variant summary

Our verdict is Benign. Variant got -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. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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:5

Conservation

PhyloP100: 0.286

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 made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 235433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-28399670-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A1	NM_080669.6 linkuse as main transcript	c.1366C>T	p.Pro456Ser	missense_variant	5/5	ENST00000612814.5	NP_542400.2
SARM1	NM_015077.4 linkuse as main transcript	c.*3384G>A		3_prime_UTR_variant	9/9	ENST00000585482.6	NP_055892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC46A1	ENST00000612814.5 linkuse as main transcript	c.1366C>T	p.Pro456Ser	missense_variant	5/5	2	NM_080669.6	ENSP00000480703	P1	Q96NT5-1
SLC46A1	ENST00000618626.1 linkuse as main transcript	c.1282C>T	p.Pro428Ser	missense_variant	4/4	1		ENSP00000483652		Q96NT5-2
SARM1	ENST00000585482.6 linkuse as main transcript	c.*3384G>A		3_prime_UTR_variant	9/9	1	NM_015077.4	ENSP00000468032	P1	Q6SZW1-1
SLC46A1	ENST00000582735.1 linkuse as main transcript	c.252C>T	p.Phe84=	synonymous_variant	2/2	4		ENSP00000463339

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

GnomAD3 exomes

AF:

0.00311

AC:

770

AN:

247576

Hom.:

AF XY:

0.00301

AC XY:

405

AN XY:

134474

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 SAS exome

AF:

0.000621

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

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000638

Gnomad4 FIN exome

AF:

0.00698

Gnomad4 NFE exome

AF:

0.00374

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.00226

AC:

344

AN:

152296

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00566

Gnomad4 NFE

AF:

0.00356

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00366

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SARM1: BS2; SLC46A1: BP4, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 03, 2015

- -

SLC46A1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

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

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

MutationTaster

Benign

0.71

D;N;N

PrimateAI

Benign

0.31

Sift4G

Benign

0.85

T;T

Polyphen

0.0

B;.

Vest4

0.047

MVP

0.25

ClinPred

0.0029

GERP RS

0.37

Varity_R

0.028

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over