chr11-49200333-T-A

Variant names:

• chr11-49200333-T-A
• rs202680
• NM_004476.3:c.333A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004476.3(FOLH1):​c.333A>T​(p.Ala111Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,608,196 control chromosomes in the GnomAD database, including 79,396 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (11305 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68091 hom.)
• Consequence: FOLH1 NM_004476.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.414
• Publications: 17 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=0.414 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOLH1	NM_004476.3	c.333A>T	p.Ala111Ala	synonymous_variant	Exon 3 of 19	ENST00000256999.7	NP_004467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOLH1	ENST00000256999.7	c.333A>T	p.Ala111Ala	synonymous_variant	Exon 3 of 19	1	NM_004476.3	ENSP00000256999.2

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55309 AN: 151860 Hom.: 11292 Cov.: 32

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.311 AC: 76763 AN: 246472 AF XY: 0.309

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.331

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.300 AC: 436987 AN: 1456218 Hom.: 68091 Cov.: 34 AF XY: 0.301 AC XY: 217988 AN XY: 724234

African (AFR) AF: 0.572 AC: 19079 AN: 33372

American (AMR) AF: 0.282 AC: 12535 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5075 AN: 26062

East Asian (EAS) AF: 0.329 AC: 13026 AN: 39558

South Asian (SAS) AF: 0.390 AC: 33504 AN: 85856

European-Finnish (FIN) AF: 0.328 AC: 17492 AN: 53292

Middle Eastern (MID) AF: 0.220 AC: 1267 AN: 5750

European-Non Finnish (NFE) AF: 0.286 AC: 316430 AN: 1107794

Other (OTH) AF: 0.309 AC: 18579 AN: 60142

GnomAD4 genome AF: 0.364 AC: 55360 AN: 151978 Hom.: 11305 Cov.: 32 AF XY: 0.366 AC XY: 27170 AN XY: 74264

African (AFR) AF: 0.561 AC: 23247 AN: 41446

American (AMR) AF: 0.291 AC: 4439 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 696 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1662 AN: 5168

South Asian (SAS) AF: 0.398 AC: 1912 AN: 4808

European-Finnish (FIN) AF: 0.330 AC: 3488 AN: 10560

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19038 AN: 67948

Other (OTH) AF: 0.316 AC: 666 AN: 2108

Alfa AF: 0.290 Hom.: 2271

Bravo AF: 0.365

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.3
DANN	Benign	0.45
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs202680; hg19: chr11-49221885; COSMIC: COSV57046617; COSMIC: COSV57046617;