rs61886492

Positions:

• chr11-49164722-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004476.3(FOLH1):​c.1423C>T​(p.His475Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0453 in 1,599,618 control chromosomes in the GnomAD database, including 1,888 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.040 (142 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1746 hom.)
• Consequence: FOLH1 NM_004476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.28

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020479858).
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLH1	NM_004476.3	c.1423C>T	p.His475Tyr	missense_variant	13/19	ENST00000256999.7	NP_004467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLH1	ENST00000256999.7	c.1423C>T	p.His475Tyr	missense_variant	13/19	1	NM_004476.3	ENSP00000256999.2

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6028 AN: 152124 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0393

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0514

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0368 AC: 8988 AN: 244002 Hom.: 201 AF XY: 0.0378 AC XY: 4989 AN XY: 132132

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0235

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.0335

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0499

Gnomad OTH exome AF: 0.0493

GnomAD4 exome AF: 0.0459 AC: 66468 AN: 1447378 Hom.: 1746 Cov.: 28 AF XY: 0.0459 AC XY: 33084 AN XY: 720100

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.0242

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0345

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0510

Gnomad4 OTH exome AF: 0.0446

GnomAD4 genome AF: 0.0396 AC: 6028 AN: 152240 Hom.: 142 Cov.: 32 AF XY: 0.0383 AC XY: 2850 AN XY: 74442

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.0372

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.0514

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0453 Hom.: 24

Bravo AF: 0.0386

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.0510 AC: 438

ExAC AF: 0.0377 AC: 4573

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.31
DEOGEN2	Benign	0.030	T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.52	T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.3	N;N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	3.3	N;N;N;N
REVEL	Benign	0.099
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.11
MPC		1.1
ClinPred		0.0037	T
GERP RS		3.5
Varity_R		0.078
gMVP		0.67

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: rs61886492; hg19: chr11-49186274; COSMIC: COSV57045628;