rs764420714

Positions:

• chr11-72195395-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016729.3(FOLR1):​c.293G>A​(p.Arg98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FOLR1 NM_016729.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.165

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2871209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLR1	NM_016729.3	c.293G>A	p.Arg98Gln	missense_variant	2/4	ENST00000393676.5	NP_057941.1
FOLR1	NM_000802.3	c.293G>A	p.Arg98Gln	missense_variant	3/5		NP_000793.1
FOLR1	NM_016724.3	c.293G>A	p.Arg98Gln	missense_variant	4/6		NP_057936.1
FOLR1	NM_016725.3	c.293G>A	p.Arg98Gln	missense_variant	3/5		NP_057937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLR1	ENST00000393676.5	c.293G>A	p.Arg98Gln	missense_variant	2/4	1	NM_016729.3	ENSP00000377281.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251430 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral folate transport deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 98 of the FOLR1 protein (p.Arg98Gln). This variant is present in population databases (rs764420714, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FOLR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 580422). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.78	.;.;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.0	M;M;M;M
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.028	D;D;D;D
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.77	P;P;P;P
Vest4		0.31
MutPred		0.51		Gain of ubiquitination at K97 (P = 0.0581);Gain of ubiquitination at K97 (P = 0.0581);Gain of ubiquitination at K97 (P = 0.0581);Gain of ubiquitination at K97 (P = 0.0581);
MVP		0.70
MPC		0.53
ClinPred		0.25	T
GERP RS		1.1
Varity_R		0.24
gMVP		0.48

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: rs764420714; hg19: chr11-71906439; COSMIC: COSV100398575;