Genetic Variant FOLH1:p.Tyr300Asn (chr11-49183171-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004476.3(FOLH1):c.898T>A(p.Tyr300Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. Y300H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FOLH1
NM_004476.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.422

Publications

0 publications found

Variant links:

Genes affected

FOLH1 (HGNC:3788): (folate hydrolase 1) This gene encodes a type II transmembrane glycoprotein belonging to the M28 peptidase family. The protein acts as a glutamate carboxypeptidase on different alternative substrates, including the nutrient folate and the neuropeptide N-acetyl-l-aspartyl-l-glutamate and is expressed in a number of tissues such as prostate, central and peripheral nervous system and kidney. A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. In the prostate the protein is up-regulated in cancerous cells and is used as an effective diagnostic and prognostic indicator of prostate cancer. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants encoding several different isoforms. [provided by RefSeq, Jul 2010]

FOLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04647672).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004476.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOLH1	NM_004476.3	MANE Select	c.898T>A	p.Tyr300Asn	missense	Exon 7 of 19	NP_004467.1	Q04609-1
FOLH1	NM_001193471.3		c.853T>A	p.Tyr285Asn	missense	Exon 8 of 20	NP_001180400.1	Q04609-7
FOLH1	NM_001014986.3		c.898T>A	p.Tyr300Asn	missense	Exon 7 of 18	NP_001014986.1	Q04609-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOLH1	ENST00000256999.7	TSL:1 MANE Select	c.898T>A	p.Tyr300Asn	missense	Exon 7 of 19	ENSP00000256999.2	Q04609-1
FOLH1	ENST00000340334.11	TSL:1	c.853T>A	p.Tyr285Asn	missense	Exon 8 of 20	ENSP00000344131.7	Q04609-7
FOLH1	ENST00000356696.7	TSL:1	c.898T>A	p.Tyr300Asn	missense	Exon 7 of 18	ENSP00000349129.3	Q04609-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.4

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.067

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.52

M_CAP

Benign

0.0026

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.77

PhyloP100

0.42

PrimateAI

Benign

0.47

PROVEAN

Benign

1.8

REVEL

Benign

0.052

Sift

Benign

0.81

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.25

MutPred

0.36

Loss of phosphorylation at Y300 (P = 0.0235)

MVP

0.20

MPC

0.56

ClinPred

0.053

GERP RS

-5.5

Varity_R

0.18

gMVP

0.61

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over