17-28405920-GC-G
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_080669.6(SLC46A1):βc.194delβ(p.Gly65AlafsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,607,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000039 ( 0 hom., cov: 32)
Exomes π: 6.9e-7 ( 0 hom. )
Consequence
SLC46A1
NM_080669.6 frameshift
NM_080669.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.129
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 17-28405920-GC-G is Pathogenic according to our data. Variant chr17-28405920-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 851.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC46A1 | NM_080669.6 | c.194del | p.Gly65AlafsTer25 | frameshift_variant | 1/5 | ENST00000612814.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC46A1 | ENST00000612814.5 | c.194del | p.Gly65AlafsTer25 | frameshift_variant | 1/5 | 2 | NM_080669.6 | P1 | |
ENST00000580714.1 | n.212+476del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455788Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 723814
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital defect of folate absorption Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 2007 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2023 | This sequence change creates a premature translational stop signal (p.Gly65Alafs*25) in the SLC46A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC46A1 are known to be pathogenic (PMID: 17446347, 21333572). 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 premature translational stop signal has been observed in individual(s) with hereditary folate malabsorption (PMID: 17446347). ClinVar contains an entry for this variant (Variation ID: 851). For these reasons, this variant has been classified as Pathogenic. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at