rs202676

Variant names:

• chr11-49206068-A-G
• rs202676
• NM_004476.3:c.223T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000256999.7(FOLH1):​c.223T>C​(p.Tyr75His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,609,292 control chromosomes in the GnomAD database, including 59,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9395 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49698 hom.)
• Consequence: FOLH1 ENST00000256999.7 missense, splice_region
• Scores: Splicing: ADA: 0.00003586
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.564
• Publications: 71 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0846725E-4).
• BP6: Variant 11-49206068-A-G is Benign according to our data. Variant chr11-49206068-A-G is described in ClinVar as Benign. ClinVar VariationId is 1287111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000256999.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLH1	NM_004476.3	MANE Select	c.223T>C	p.Tyr75His	missense splice_region	Exon 2 of 19	NP_004467.1
	FOLH1	NM_001193471.3		c.178T>C	p.Tyr60His	missense splice_region	Exon 3 of 20	NP_001180400.1
	FOLH1	NM_001014986.3		c.223T>C	p.Tyr75His	missense splice_region	Exon 2 of 18	NP_001014986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLH1	ENST00000256999.7	TSL:1 MANE Select	c.223T>C	p.Tyr75His	missense splice_region	Exon 2 of 19	ENSP00000256999.2
	FOLH1	ENST00000340334.11	TSL:1	c.178T>C	p.Tyr60His	missense splice_region	Exon 3 of 20	ENSP00000344131.7
	FOLH1	ENST00000356696.7	TSL:1	c.223T>C	p.Tyr75His	missense splice_region	Exon 2 of 18	ENSP00000349129.3

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49330 AN: 151958 Hom.: 9382 Cov.: 33

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.277 AC: 69023 AN: 248876 AF XY: 0.274

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.303

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.253 AC: 368527 AN: 1457216 Hom.: 49698 Cov.: 32 AF XY: 0.254 AC XY: 183966 AN XY: 724820

African (AFR) AF: 0.542 AC: 18062 AN: 33328

American (AMR) AF: 0.259 AC: 11433 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4535 AN: 25928

East Asian (EAS) AF: 0.329 AC: 13011 AN: 39504

South Asian (SAS) AF: 0.355 AC: 30351 AN: 85390

European-Finnish (FIN) AF: 0.289 AC: 15307 AN: 52920

Middle Eastern (MID) AF: 0.191 AC: 1094 AN: 5742

European-Non Finnish (NFE) AF: 0.233 AC: 258876 AN: 1110030

Other (OTH) AF: 0.263 AC: 15858 AN: 60192

GnomAD4 genome AF: 0.325 AC: 49381 AN: 152076 Hom.: 9395 Cov.: 33 AF XY: 0.327 AC XY: 24351 AN XY: 74356

African (AFR) AF: 0.532 AC: 22039 AN: 41450

American (AMR) AF: 0.253 AC: 3872 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3470

East Asian (EAS) AF: 0.321 AC: 1660 AN: 5170

South Asian (SAS) AF: 0.358 AC: 1726 AN: 4820

European-Finnish (FIN) AF: 0.296 AC: 3131 AN: 10560

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15572 AN: 68000

Other (OTH) AF: 0.266 AC: 561 AN: 2108

Alfa AF: 0.253 Hom.: 7370

Bravo AF: 0.326

TwinsUK AF: 0.238 AC: 884

ALSPAC AF: 0.242 AC: 933

ESP6500AA AF: 0.524 AC: 2305

ESP6500EA AF: 0.224 AC: 1924

ExAC AF: 0.281 AC: 34140

Asia WGS AF: 0.384 AC: 1330 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.21
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.00021	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N
PhyloP100		0.56
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.015
Sift	Benign	0.22	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.089
MPC		0.44
ClinPred		0.0013	T
GERP RS		1.9
Varity_R		0.16
gMVP		0.60
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0060
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: rs202676; hg19: chr11-49227620; COSMIC: COSV57047839;