chr17-28405231-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_080669.6(SLC46A1):​c.466G>T​(p.Asp156Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D156H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SLC46A1
NM_080669.6 missense

Scores

9
4
2

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.50

Publications

15 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 Gene-Disease associations (from GenCC):
  • hereditary folate malabsorption
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a mutagenesis_site 2-fold reduction of methotrexate uptake. (size 0) in uniprot entity PCFT_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC46A1NM_080669.6 linkc.466G>T p.Asp156Tyr missense_variant Exon 2 of 5 ENST00000612814.5 NP_542400.2 Q96NT5-1A0A024QZ15

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC46A1ENST00000612814.5 linkc.466G>T p.Asp156Tyr missense_variant Exon 2 of 5 2 NM_080669.6 ENSP00000480703.1 Q96NT5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1440194
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
714894
African (AFR)
AF:
0.00
AC:
0
AN:
32882
American (AMR)
AF:
0.00
AC:
0
AN:
40344
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25714
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38328
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83664
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51806
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1102044
Other (OTH)
AF:
0.00
AC:
0
AN:
59670
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not provided Other:1
-
UniProtKB/Swiss-Prot
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;.;T;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.84
T;T;T;T
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Uncertain
0.49
D
PhyloP100
7.5
PrimateAI
Uncertain
0.73
T
Sift4G
Pathogenic
0.0
D;D;.;.
Polyphen
1.0
D;D;.;.
Vest4
0.93
MutPred
0.74
Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;.;
MVP
0.94
ClinPred
0.99
D
GERP RS
5.5
PromoterAI
-0.0090
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.77
gMVP
0.88
Mutation Taster
=3/97
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281875210; hg19: chr17-26732249; API