rs201837257

Positions:

• chr17-28405074-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_080669.6(SLC46A1):​c.623A>T​(p.Tyr208Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00158 in 1,613,990 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: SLC46A1 NM_080669.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 4.70

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042482734).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00084 (128/152304) while in subpopulation NFE AF= 0.00132 (90/68014). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC46A1	NM_080669.6	c.623A>T	p.Tyr208Phe	missense_variant	2/5	ENST00000612814.5	NP_542400.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC46A1	ENST00000612814.5	c.623A>T	p.Tyr208Phe	missense_variant	2/5	2	NM_080669.6	ENSP00000480703	P1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000767 AC: 191 AN: 249100 Hom.: 0 AF XY: 0.000695 AC XY: 94 AN XY: 135180

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.00165 AC: 2418 AN: 1461686 Hom.: 5 Cov.: 31 AF XY: 0.00156 AC XY: 1135 AN XY: 727128

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74468

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.000899

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000501 AC: 2

ESP6500EA AF: 0.00180 AC: 15

ExAC AF: 0.000728 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital defect of folate absorption Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 03, 2015

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.623A>T (p.Y208F) alteration is located in exon 2 (coding exon 2) of the SLC46A1 gene. This alteration results from a A to T substitution at nucleotide position 623, causing the tyrosine (Y) at amino acid position 208 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 208 of the SLC46A1 protein (p.Tyr208Phe). This variant is present in population databases (rs201837257, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SLC46A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 252777). 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. 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. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.33	T;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0096
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.20	T;T;.;.
Polyphen		0.039	B;B;.;.
Vest4		0.42
MVP		0.58
ClinPred		0.011	T
GERP RS		4.1
Varity_R		0.18
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs201837257; hg19: chr17-26732092;