11-72135924-CTCTGACTGTGGCTCTCTGGCAGGAATAGATGGACA-C

Position:

• chr11-72135924-CTCTGACTGTGGCTCTCTGGCAGGAATAGATGGACA-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_000804.4(FOLR3):​c.-6-21_8del variant causes a splice acceptor, coding sequence, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 152,198 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOLR3 NM_000804.4 splice_acceptor, coding_sequence, 5_prime_UTR, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.657

Genes affected

FOLR3 (HGNC:3795): (folate receptor gamma) This gene encodes a member of the folate receptor (FOLR) family of proteins, which have a high affinity for folic acid and for several reduced folic acid derivatives, and mediate delivery of 5-methyltetrahydrofolate to the interior of cells. Expression of this gene may be elevated in ovarian and primary peritoneal carcinoma. This gene is present in a gene cluster on chromosome 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.23441735 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.8, offset of -11, new splice context is: ttgtctacctggcctggcAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 11-72135924-CTCTGACTGTGGCTCTCTGGCAGGAATAGATGGACA-C is Benign according to our data. Variant chr11-72135924-CTCTGACTGTGGCTCTCTGGCAGGAATAGATGGACA-C is described in ClinVar as [Likely_benign]. Clinvar id is 3053790.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLR3	NM_000804.4	c.-6-21_8del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/5	ENST00000611028.3	NP_000795.2
FOLR3	NR_178088.1	n.45-21_58del		splice_acceptor_variant, non_coding_transcript_exon_variant, intron_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLR3	ENST00000611028.3	c.-6-21_8del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	2/5	1	NM_000804.4	ENSP00000481114	P1
FOLR3	ENST00000612844.4	c.-6-21_8del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant, NMD_transcript_variant	2/5	1		ENSP00000481027
FOLR3	ENST00000546166.1	c.-33_2del		start_lost, 5_prime_UTR_variant	1/2	3		ENSP00000446279
FOLR3	ENST00000622388.4	c.-6-21_8del		splice_acceptor_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	3/6	5		ENSP00000481833

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 152082 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00100 AC: 248 AN: 247764 Hom.: 1 AF XY: 0.000803 AC XY: 108 AN XY: 134420

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.0000555

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000724

Gnomad OTH exome AF: 0.00166

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00150 AC: 2192 AN: 1460424 Hom.: 1 AF XY: 0.00142 AC XY: 1031 AN XY: 726564

Gnomad4 AFR exome AF: 0.00877

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152198 Hom.: 3 Cov.: 31 AF XY: 0.00285 AC XY: 212 AN XY: 74424

Gnomad4 AFR AF: 0.00747

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00201 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FOLR3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs541632103; hg19: chr11-71846970;