Genetic Variant FOLR1:c.493+2T>C (chr11-72195749-T-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

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:1U:7B:6

Conservation

PhyloP100: 4.31

Publications

16 publications found

Variant links:

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]

FOLR1 Gene-Disease associations (from GenCC):

neurodegenerative syndrome due to cerebral folate transport deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

FOLR1 links:

ENSG00000204971 (HGNC:58347):

ENSG00000204971 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 95750.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016729.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FOLR1	NM_016729.3	MANE Select	c.493+2T>C	splice_donor intron	N/A	NP_057941.1	P15328
FOLR1	NM_000802.3		c.493+2T>C	splice_donor intron	N/A	NP_000793.1	P15328
FOLR1	NM_016724.3		c.493+2T>C	splice_donor intron	N/A	NP_057936.1	P15328

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FOLR1	ENST00000393676.5	TSL:1 MANE Select	c.493+2T>C	splice_donor intron	N/A	ENSP00000377281.3	P15328
FOLR1	ENST00000312293.9	TSL:1	c.493+2T>C	splice_donor intron	N/A	ENSP00000308137.4	P15328
FOLR1	ENST00000393679.5	TSL:1	c.493+2T>C	splice_donor intron	N/A	ENSP00000377284.1	P15328

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

151956

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00338

AC:

849

AN:

251382

AF XY:

0.00405

show subpopulations

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 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.:

Cov.:

AF XY:

0.00319

AC XY:

2319

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00681

AC:

178

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0130

AC:

1118

AN:

86258

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00222

AC:

2467

AN:

1112006

Other (OTH)

AF:

0.00346

AC:

209

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

291

582

874

1165

1456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152074

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000434

AC:

AN:

41486

American (AMR)

AF:

0.000917

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0137

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000662

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00203

AC:

138

AN:

67976

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00168

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00343

AC:

416

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00273

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cerebral folate transport deficiency (6)

not provided (5)

FOLR1-related disorder (1)

Inborn genetic diseases (1)

Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

PhyloP100

4.3

GERP RS

5.1

Mutation Taster

=40/39

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over