rs1555069069

Variant names:

• chr11-72195359-G-A
• rs1555069069
• NM_016729.3:c.257G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-72195359-G-A
• chr11-72195359-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016729.3(FOLR1):​c.257G>A​(p.Trp86*) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOLR1 NM_016729.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.71
• Publications: 0 publications found

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

ENSG00000204971 (HGNC:58347):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72195359-G-A is Pathogenic according to our data. Variant chr11-72195359-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 470723.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLR1	NM_016729.3	MANE Select	c.257G>A	p.Trp86*	stop_gained	Exon 2 of 4	NP_057941.1	P15328
	FOLR1	NM_000802.3		c.257G>A	p.Trp86*	stop_gained	Exon 3 of 5	NP_000793.1	P15328
	FOLR1	NM_016724.3		c.257G>A	p.Trp86*	stop_gained	Exon 4 of 6	NP_057936.1	P15328

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLR1	ENST00000393676.5	TSL:1 MANE Select	c.257G>A	p.Trp86*	stop_gained	Exon 2 of 4	ENSP00000377281.3	P15328
	FOLR1	ENST00000312293.9	TSL:1	c.257G>A	p.Trp86*	stop_gained	Exon 3 of 5	ENSP00000308137.4	P15328
	FOLR1	ENST00000393679.5	TSL:1	c.257G>A	p.Trp86*	stop_gained	Exon 3 of 5	ENSP00000377284.1	P15328

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebral folate transport deficiency (1)

Computational scores

Source: dbNSFP v4.9

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	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.7
Vest4		0.86
GERP RS		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555069069; hg19: chr11-71906403;