chr11-49171214-C-G

Variant names:

• chr11-49171214-C-G
• rs370887055
• NM_004476.3:c.1289G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004476.3(FOLH1):​c.1289G>C​(p.Gly430Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000042 in 1,430,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G430D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: FOLH1 NM_004476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.21
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLH1	NM_004476.3	MANE Select	c.1289G>C	p.Gly430Ala	missense	Exon 11 of 19	NP_004467.1	Q04609-1
	FOLH1	NM_001193471.3		c.1244G>C	p.Gly415Ala	missense	Exon 12 of 20	NP_001180400.1	Q04609-7
	FOLH1	NM_001014986.3		c.1289G>C	p.Gly430Ala	missense	Exon 11 of 18	NP_001014986.1	Q04609-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLH1	ENST00000256999.7	TSL:1 MANE Select	c.1289G>C	p.Gly430Ala	missense	Exon 11 of 19	ENSP00000256999.2	Q04609-1
	FOLH1	ENST00000340334.11	TSL:1	c.1244G>C	p.Gly415Ala	missense	Exon 12 of 20	ENSP00000344131.7	Q04609-7
	FOLH1	ENST00000356696.7	TSL:1	c.1289G>C	p.Gly430Ala	missense	Exon 11 of 18	ENSP00000349129.3	Q04609-8

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000420 AC: 6 AN: 1430188 Hom.: 0 Cov.: 31 AF XY: 0.00000703 AC XY: 5 AN XY: 710876

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31132

American (AMR) AF: 0.00 AC: 0 AN: 38570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24956

East Asian (EAS) AF: 0.00 AC: 0 AN: 38936

South Asian (SAS) AF: 0.00 AC: 0 AN: 79430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1100190

Other (OTH) AF: 0.00 AC: 0 AN: 58936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000104408), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.89		Loss of disorder (P = 0.1353)
MVP		0.93
MPC		2.2
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.97
Mutation Taster		=20/80	disease causing

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: rs370887055; hg19: chr11-49192766;