11-72190447-G-A

Variant names:

• chr11-72190447-G-A
• rs1540087
• ENST00000393679.5:c.-203G>A

Variant summary

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

The ENST00000393679.5(FOLR1):​c.-203G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 152,272 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (206 hom., cov: 32)
  • Exomes 𝑓: 0.042 (0 hom.)
• Consequence: FOLR1 ENST00000393679.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800
• Publications: 12 publications found

Genes affected

FOLR1 (HGNC:3791): (folate receptor alpha) The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

FOLR1 Gene-Disease associations (from GenCC):

• neurodegenerative syndrome due to cerebral folate transport deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ENSG00000204971 (HGNC:58347):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-72190447-G-A is Benign according to our data. Variant chr11-72190447-G-A is described in ClinVar as Benign. ClinVar VariationId is 1296043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0899 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000393679.5. 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
	FOLR1	NM_000802.3		c.-9+516G>A		intron	N/A	NP_000793.1
	FOLR1	NM_016724.3		c.-74-129G>A		intron	N/A	NP_057936.1
	FOLR1	NM_016725.3		c.-9+688G>A		intron	N/A	NP_057937.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOLR1	ENST00000393679.5	TSL:1	c.-203G>A		5_prime_UTR	Exon 1 of 5	ENSP00000377284.1
	FOLR1	ENST00000312293.9	TSL:1	c.-9+688G>A		intron	N/A	ENSP00000308137.4
	FOLR1	ENST00000393681.6	TSL:1	c.-74-129G>A		intron	N/A	ENSP00000377286.2

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5812 AN: 152106 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0790

Gnomad SAS AF: 0.0648

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00960

Gnomad OTH AF: 0.0312

GnomAD4 exome AF: 0.0417 AC: 2 AN: 48 Hom.: 0 Cov.: 0 AF XY: 0.0500 AC XY: 2 AN XY: 40

⚠️ 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: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0526 AC: 2 AN: 38

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0382 AC: 5819 AN: 152224 Hom.: 206 Cov.: 32 AF XY: 0.0393 AC XY: 2923 AN XY: 74434

African (AFR) AF: 0.0924 AC: 3836 AN: 41524

American (AMR) AF: 0.0197 AC: 301 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.0790 AC: 409 AN: 5180

South Asian (SAS) AF: 0.0646 AC: 312 AN: 4826

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00961 AC: 654 AN: 68026

Other (OTH) AF: 0.0304 AC: 64 AN: 2108

Alfa AF: 0.0206 Hom.: 102

Bravo AF: 0.0408

Asia WGS AF: 0.0560 AC: 196 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.46
PhyloP100		0.080
PromoterAI		0.013	Neutral
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: rs1540087; hg19: chr11-71901491;