chr11-72195911-G-A

Position:

chr11-72195911-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_016729.3(FOLR1):c.508G>A(p.Ala170Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,614,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A170S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

FOLR1
NM_016729.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 2.42

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065000057).

BP6

Variant 11-72195911-G-A is Benign according to our data. Variant chr11-72195911-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205460.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FOLR1	NM_016729.3 linkuse as main transcript	c.508G>A	p.Ala170Thr	missense_variant	4/4	ENST00000393676.5
FOLR1	NM_000802.3 linkuse as main transcript	c.508G>A	p.Ala170Thr	missense_variant	5/5
FOLR1	NM_016724.3 linkuse as main transcript	c.508G>A	p.Ala170Thr	missense_variant	6/6
FOLR1	NM_016725.3 linkuse as main transcript	c.508G>A	p.Ala170Thr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOLR1	ENST00000393676.5 linkuse as main transcript	c.508G>A	p.Ala170Thr	missense_variant	4/4	1	NM_016729.3	P1
	ENST00000378140.3 linkuse as main transcript	n.419+2602C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

235

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00543

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000370

AC:

AN:

251464

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00498

Gnomad AMR exome

AF:

0.000260

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00529

Gnomad4 AMR exome

AF:

0.000268

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:

0.0000234

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00154

AC:

235

AN:

152320

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00541

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000472

Hom.:

Bravo

AF:

0.00179

ESP6500AA

AF:

0.00500

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2020	- -

Cerebral folate transport deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 03, 2019

- -

FOLR1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2020

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). -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.91

.;.;.;D

MetaRNN

Benign

0.0065

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.040

N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.072

B;B;B;B

Vest4

0.16

MVP

0.65

MPC

0.52

ClinPred

0.059

GERP RS

4.1

Varity_R

0.28

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over