11-72196042-G-A

Position:

• chr11-72196042-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_016729.3(FOLR1):​c.639G>A​(p.Trp213Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOLR1 NM_016729.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.72

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.174 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72196042-G-A is Pathogenic according to our data. Variant chr11-72196042-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 588895.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLR1	NM_016729.3	c.639G>A	p.Trp213Ter	stop_gained	4/4	ENST00000393676.5	NP_057941.1
FOLR1	NM_000802.3	c.639G>A	p.Trp213Ter	stop_gained	5/5		NP_000793.1
FOLR1	NM_016724.3	c.639G>A	p.Trp213Ter	stop_gained	6/6		NP_057936.1
FOLR1	NM_016725.3	c.639G>A	p.Trp213Ter	stop_gained	5/5		NP_057937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLR1	ENST00000393676.5	c.639G>A	p.Trp213Ter	stop_gained	4/4	1	NM_016729.3	ENSP00000377281	P1
	ENST00000378140.3	n.419+2471C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2017

The p.W213* variant (also known as c.639G>A), located in coding exon 4 of the FOLR1 gene, results from a G to A substitution at nucleotide position 639. This changes the amino acid from a tryptophan to a stop codon within coding exon 4. This alteration is expected to result in loss of function by premature protein truncation. This variant truncates a domain indicated to be important for protein function (Chen C et al. Nature, 2013 Aug;500:486-9; Grapp M et al. Brain, 2012 Jul;135:2022-31; Golani LK et al. J. Med. Chem., 2016 Sep;59:7856-76; Kelemen LE. Int. J. Cancer, 2006 Jul;119:243-50; Wibowo AS et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Sep;110:15180-8; Yan W et al. Biochemistry, 1995 Nov;34:14594-600). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	D;D;D;D
Vest4		0.81
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757554598; hg19: chr11-71907086;