rs1057524829

Variant names:

• chr11-72192174-A-G
• rs1057524829
• NM_016729.3:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-72192174-A-G
• chr11-72192174-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_016729.3(FOLR1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOLR1 NM_016729.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.60
• 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ENSG00000204971 (HGNC:58347):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 5 codons. Genomic position: 72192186. Lost 0.017 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72192174-A-G is Pathogenic according to our data. Variant chr11-72192174-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 393190.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.1A>G	p.Met1?	start_lost	Exon 1 of 4	NP_057941.1	P15328
	FOLR1	NM_000802.3		c.1A>G	p.Met1?	start_lost	Exon 2 of 5	NP_000793.1	P15328
	FOLR1	NM_016724.3		c.1A>G	p.Met1?	start_lost	Exon 3 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.1A>G	p.Met1?	start_lost	Exon 1 of 4	ENSP00000377281.3	P15328
	FOLR1	ENST00000312293.9	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 2 of 5	ENSP00000308137.4	P15328
	FOLR1	ENST00000393679.5	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 2 of 5	ENSP00000377284.1	P15328

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.42	T
PhyloP100		2.6
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.72
MutPred		0.67		Gain of methylation at R4 (P = 0.0976)
MVP		0.85
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.048	Neutral
Varity_R		0.88
gMVP		0.66
Mutation Taster		=104/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1057524829; hg19: chr11-71903218;