17-28402322-C-T

Position:

• chr17-28402322-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_080669.6(SLC46A1):​c.1082-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000124 in 1,612,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC46A1 NM_080669.6 splice_acceptor
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 6.81

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.060144927 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of 27, new splice context is: gttgcttttcctgtcattAGtca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-28402322-C-T is Pathogenic according to our data. Variant chr17-28402322-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A1	NM_080669.6	c.1082-1G>A		splice_acceptor_variant		ENST00000612814.5	NP_542400.2
SARM1	NM_015077.4	c.*6036C>T		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	c.1082-1G>A		splice_acceptor_variant		2	NM_080669.6	ENSP00000480703	P1
SARM1	ENST00000585482.6	c.*6036C>T		3_prime_UTR_variant	9/9	1	NM_015077.4	ENSP00000468032	P1
SLC46A1	ENST00000618626.1	c.1082-1556G>A		intron_variant		1		ENSP00000483652
SLC46A1	ENST00000582735.1	c.206+2294G>A		intron_variant		4		ENSP00000463339

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460342 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000135

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000162

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital defect of folate absorption Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 05, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	literature only	GeneReviews	-	In-frame deletion resulting from skipping of exon 3 was detected in cDNA from transformed lymphocytes of individuals with HFM (Qiu et al 2006); the resulting transcript variant is BC01069.1. The same pathogenic variant identified in a total of ten unrelated families of Puerto Rican ancestry (Qiu et al 2006, Borzutzky et al 2009, Mahadeo et al 2011, Zhao et al 2017). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2024	Variant summary: SLC46A1 c.1082-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Three predict the variant creates a 3' cryptic acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in skipping of exon 3 and consequent in-frame deletion (Qiu_2006). The variant allele was found at a frequency of 4.1e-06 in 244488 control chromosomes (gnomAD). c.1082-1G>A has been reported in the literature in multiple individuals affected with Congenital Defect Of Folate Absorption (Qiu_2006, Mahadeo_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in reduced protein expression and trapped intracellularly without detectable localization to the cell membrane (Qiu_2006). The following publications have been ascertained in the context of this evaluation (PMID: 21489556, 17129779). ClinVar contains an entry for this variant (Variation ID: 850). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	Published functional studies demonstrate a damaging effect on transport function (Qiu et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 17129779, 11807405, 20301716, 22454052, 23816405, 19740703, 20005757, 19176287, 21489556) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change affects an acceptor splice site in intron 2 of the SLC46A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs80338775, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with hereditary folate malabsorption syndrome (PMID: 17129779, 19740703, 21489556). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Tyr362_Gly389del. ClinVar contains an entry for this variant (Variation ID: 850). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects SLC46A1 function (PMID: 17129779). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 17129779). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.1082-1G>A intronic alteration consists of a G to A substitution one nucleotide before exon 3 (coding exon 3) of the SLC46A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/275882) total alleles studied. This variant has been identified in the homozygous state in multiple individuals diagnosed with hereditary folate malabsorption (Mahadeo, 2011; Borzutzky, 2009; Geller, 2002). This nucleotide position is highly conserved in available vertebrate species. RNA studies demonstrate this alteration leads to abnormal splicing in the set of samples tested (Qiu, 2006). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

SLC46A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The SLC46A1 c.1082-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This is the most commonly reported causative variant in the SLC46A1 gene; it has been documented in many individuals of Puerto Rican descent (Mahadeo et al. 2011. PubMed ID: 21489556). This variant has been shown to lead to skipping of exon 3 and an in-frame deletion of 28 amino acids (p.Tyr362_Gly389del, Qiu et al. 2006. PubMed ID: 17129779, referred to as G>A at position 5882 in GenBank accession DQ496103). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338775; hg19: chr17-26729340;