dbSNP rs61735636: FOLR1:p.Asn131Lys (chr11-72195647-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016729.3(FOLR1):c.393C>G(p.Asn131Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N131D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FOLR1
NM_016729.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.66

Publications

0 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P

FOLR1 links:

ENSG00000204971 (HGNC:58347):

ENSG00000204971 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOLR1	NM_016729.3 link	c.393C>G	p.Asn131Lys	missense_variant	Exon 3 of 4	ENST00000393676.5	NP_057941.1	P15328A0A024R5H1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOLR1	ENST00000393676.5 link	c.393C>G	p.Asn131Lys	missense_variant	Exon 3 of 4	1	NM_016729.3	ENSP00000377281.3		P15328

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.0090

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.35

T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.87

.;.;.;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.4

M;M;M;M

PhyloP100

-2.7

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D

Polyphen

0.81

P;P;P;P

Vest4

0.48

MutPred

0.44

Gain of ubiquitination at N131 (P = 0.0369);Gain of ubiquitination at N131 (P = 0.0369);Gain of ubiquitination at N131 (P = 0.0369);Gain of ubiquitination at N131 (P = 0.0369);

MVP

0.39

MPC

0.92

ClinPred

0.62

GERP RS

-8.2

Varity_R

0.29

gMVP

0.69

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over