11-72195749-T-C

Position:

• chr11-72195749-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_016729.3(FOLR1):​c.493+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00272 in 1,613,960 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (30 hom.)
• Consequence: FOLR1 NM_016729.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:6
• Conservation: PhyloP100: 4.31

Genes affected

FOLR1 (HGNC:3791): (folate receptor alpha) The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

ENSG00000204971 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.1, offset of 44, new splice context is: gagGTgtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 11-72195749-T-C is Benign according to our data. Variant chr11-72195749-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95750.We mark this variant Likely_benign, oryginal submissions are: {Pathogenic=1, Uncertain_significance=5, Benign=5}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00176 (268/152074) while in subpopulation SAS AF= 0.0137 (66/4804). AF 95% confidence interval is 0.0111. There are 1 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLR1	NM_016729.3	c.493+2T>C		splice_donor_variant, intron_variant		ENST00000393676.5	NP_057941.1
FOLR1	NM_000802.3	c.493+2T>C		splice_donor_variant, intron_variant			NP_000793.1
FOLR1	NM_016724.3	c.493+2T>C		splice_donor_variant, intron_variant			NP_057936.1
FOLR1	NM_016725.3	c.493+2T>C		splice_donor_variant, intron_variant			NP_057937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLR1	ENST00000393676.5	c.493+2T>C		splice_donor_variant, intron_variant		1	NM_016729.3	ENSP00000377281.3

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 151956 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00338 AC: 849 AN: 251382 Hom.: 8 AF XY: 0.00405 AC XY: 550 AN XY: 135870

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0140

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00282 AC: 4117 AN: 1461886 Hom.: 30 Cov.: 33 AF XY: 0.00319 AC XY: 2319 AN XY: 727244

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00681

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152074 Hom.: 1 Cov.: 33 AF XY: 0.00219 AC XY: 163 AN XY: 74338

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.000662

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00168

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00343 AC: 416

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cerebral folate transport deficiency Pathogenic:1 Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Pathogenic, flagged submission	literature only	OMIM	Sep 21, 2011	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous c.493+2T>C variant in FOLR1 and has been identified in at least 1 individual with intellectual disability (PMID: 21937992), and has been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive folate receptor deficiency. -
Benign, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice donor variant c.493+2T>C in FOLR1 (NM_016725.3) has been reported previously as homozygous in three siblings from a consanguineous family with symptoms of cerebral folate transport deficiency (Najmabadi H et al, 2011). It has also been recently reported in trans with a pathogenic variant in an adult patient with stable clinical and MRI features.The c.493+2T>C variant is observed in 430/30,614 (1.4046%) alleles from individuals of South Asian background in gnomAD Exomes and in 13/978 (1.3292%) alleles from individuals of South Asian background in 1000 Genomes. It has been observed in homozygous state in gnomad database in multiple individuals. Considering the high frequency of the variant the possibility that it is disease causing is unlikely and hence the variant has been classified as Benign. -

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2023	The c.493+2T>C variant in FOLR1 has been reported in at least 3 individuals with neurologic disease (Najmabadi 2011 PMID: 21937992, McCreary 2019 PMID: 31664448, Hiz Kurul 2022 PMID: 34791078). It has also been identified in 1.4% (430/30614) of South Asian chromosomes by gnomAD including 8 homozygotes (http://gnomad.broadinstitute.org, v.2.1.2), which is higher than expected for a disease-causing variant in FOLR1. This variant has also been reported in ClinVar (Variation ID 95750). This variant occurs within the canonical splice site (+/- 1,2) of the last intron of the FOLR1 gene and is predicted to cause altered splicing. In summary, due to the conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Strong, BS1. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FOLR1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2019	This variant is associated with the following publications: (PMID: 31664448, 29961769, 29661558, 27535533, 27884173, 21937992) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2019

The c.493+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 3 in the FOLR1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In one study, this alteration was detected as homozygous in three siblings from a consanguineous family with symptoms of cerebral folate transport deficiency (Najmabadi H et al. Nature, 2011 Oct;478:57-63). This variant occurred in the homozygous state in a reportedly healthy mother of three heterozygous daughters, one described as having clinical Rett syndrome, and two with autism and epilepsy (Ramaekers VT et al. Mol Genet Metab. 2018 May;124(1):87-93). Based on data from gnomAD, this variant has an overall frequency of approximately 0.31% (861/277102) and has been seen as homozygous in 10 individuals. The highest observed frequency was 1.4% (434/30780) in the South Asian subpopulation. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Seizure Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 25, 2017

- -

FOLR1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.45		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144637717; hg19: chr11-71906793;