rs281875211

Positions:

chr17-28402276-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_080669.6(SLC46A1):c.1127G>A(p.Arg376Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SLC46A1
NM_080669.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:2

Conservation

PhyloP100: 5.11

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-28402277-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

PP5

Variant 17-28402276-C-T is Pathogenic according to our data. Variant chr17-28402276-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65749.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=2, Pathogenic=2}. Variant chr17-28402276-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A1	NM_080669.6 linkuse as main transcript	c.1127G>A	p.Arg376Gln	missense_variant	3/5	ENST00000612814.5	NP_542400.2	Q96NT5-1A0A024QZ15
SARM1	NM_015077.4 linkuse as main transcript	c.*5990C>T		3_prime_UTR_variant	9/9	ENST00000585482.6	NP_055892.2	Q6SZW1-1Q05B42Q0D2N8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC46A1	ENST00000612814.5 linkuse as main transcript	c.1127G>A	p.Arg376Gln	missense_variant	3/5	2	NM_080669.6	ENSP00000480703.1	Q96NT5-1
SARM1	ENST00000585482.6 linkuse as main transcript	c.*5990C>T		3_prime_UTR_variant	9/9	1	NM_015077.4	ENSP00000468032.2	Q6SZW1-1
SLC46A1	ENST00000618626.1 linkuse as main transcript	c.1082-1510G>A		intron_variant		1		ENSP00000483652.1	Q96NT5-2
SLC46A1	ENST00000582735.1 linkuse as main transcript	c.205+2340G>A		intron_variant		4		ENSP00000463339.1	J3QL21

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

246306

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital defect of folate absorption

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary folate malabsorption (MIM#229050). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 9 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0601 - Variant is located in the well-established functional 10th transmembrane domain. This residue is crucial for folate uptake (PMID: 20686069). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg376Trp) has been reported in at least two other individuals with hereditary folate malabsorption (PMID: 27664775). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in two homozygotes with hereditary folate malabsorption (ClinVar, PMID: 20686069). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies using transfected cells demonstrated impaired folate uptake (PMID: 20686069). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jul 30, 2024	The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20686069). The variant was found homozygous in an affected individual (3billion dataset). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000065749). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 20686069 / 3billion dataset). A different missense change at the same codon (p.Arg376Trp) has been reported to be associated with SLC46A1-related disorder (ClinVar ID: VCV000000854 / PMID: 17446347). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 376 of the SLC46A1 protein (p.Arg376Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive hereditary folate malabsorption (PMID: 21489556). ClinVar contains an entry for this variant (Variation ID: 65749). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC46A1 protein function. Experimental studies have shown that this missense change affects SLC46A1 function (PMID: 20686069). This variant disrupts the p.Arg376 amino acid residue in SLC46A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC46A1-related conditions (PMID: 17446347), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

-0.022

PrimateAI

Benign

0.41

Sift4G

Uncertain

0.014

Polyphen

0.99

Vest4

0.91

MVP

0.58

ClinPred

0.99

GERP RS

5.7

Varity_R

0.80

gMVP

0.93

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