rs202676

Positions:

• chr11-49206068-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004476.3(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. 16/22 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (9395 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49698 hom.)
• Consequence: FOLH1 NM_004476.3 missense, splice_region
• Scores: Splicing: ADA: 0.00003586
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.564

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLH1	NM_004476.3	c.223T>C	p.Tyr75His	missense_variant, splice_region_variant	2/19	ENST00000256999.7	NP_004467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLH1	ENST00000256999.7	c.223T>C	p.Tyr75His	missense_variant, splice_region_variant	2/19	1	NM_004476.3	ENSP00000256999	P1

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

GnomAD3 exomes AF: 0.277 AC: 69023 AN: 248876 Hom.: 10610 AF XY: 0.274 AC XY: 36918 AN XY: 134626

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 SAS exome AF: 0.362

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

Gnomad4 AFR exome AF: 0.542

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.329

Gnomad4 SAS exome AF: 0.355

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.263

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

Gnomad4 AFR AF: 0.532

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.229

Gnomad4 OTH AF: 0.266

Alfa AF: 0.250 Hom.: 4011

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2020	This variant is associated with the following publications: (PMID: 22021659) -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
MetaRNN	Benign	0.00021	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	N;N;.;.;.
MutationTaster	Benign	0.99	P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.46	N;N;N;N;N
REVEL	Benign	0.015
Sift	Benign	0.22	T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.089
MPC		0.44
ClinPred		0.0013	T
GERP RS		1.9
Varity_R		0.16
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs202676; hg19: chr11-49227620; COSMIC: COSV57047839;