11-72139084-C-T

Position:

• chr11-72139084-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000804.4(FOLR3):​c.292C>T​(p.Arg98Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,594,208 control chromosomes in the GnomAD database, including 2,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.040 (125 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1895 hom.)
• Consequence: FOLR3 NM_000804.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.26

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039766133).
• BP6: Variant 11-72139084-C-T is Benign according to our data. Variant chr11-72139084-C-T is described in ClinVar as [Benign]. Clinvar id is 3035503.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOLR3	NM_000804.4	c.292C>T	p.Arg98Cys	missense_variant	3/5	ENST00000611028.3	NP_000795.2
FOLR3	NR_178088.1	n.470C>T		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOLR3	ENST00000611028.3	c.292C>T	p.Arg98Cys	missense_variant	3/5	1	NM_000804.4	ENSP00000481114	P1
FOLR3	ENST00000612844.4	c.420C>T	p.Ser140=	synonymous_variant, NMD_transcript_variant	3/5	1		ENSP00000481027
FOLR3	ENST00000622388.4	c.292C>T	p.Arg98Cys	missense_variant	4/6	5		ENSP00000481833

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 5344 AN: 132416 Hom.: 125 Cov.: 33

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00383

Gnomad AMR AF: 0.0518

Gnomad ASJ AF: 0.0414

Gnomad EAS AF: 0.000467

Gnomad SAS AF: 0.0347

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0374

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0530

GnomAD3 exomes AF: 0.0350 AC: 8787 AN: 251052 Hom.: 209 AF XY: 0.0360 AC XY: 4887 AN XY: 135702

Gnomad AFR exome AF: 0.00925

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0405

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0262

Gnomad FIN exome AF: 0.0338

Gnomad NFE exome AF: 0.0494

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0483 AC: 70635 AN: 1461662 Hom.: 1895 Cov.: 30 AF XY: 0.0478 AC XY: 34765 AN XY: 727110

Gnomad4 AFR exome AF: 0.00884

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0390

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0270

Gnomad4 FIN exome AF: 0.0329

Gnomad4 NFE exome AF: 0.0549

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.0403 AC: 5343 AN: 132546 Hom.: 125 Cov.: 33 AF XY: 0.0393 AC XY: 2507 AN XY: 63734

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.0517

Gnomad4 ASJ AF: 0.0414

Gnomad4 EAS AF: 0.000468

Gnomad4 SAS AF: 0.0346

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0574

Gnomad4 OTH AF: 0.0513

Alfa AF: 0.0437 Hom.: 101

Bravo AF: 0.0340

TwinsUK AF: 0.0491 AC: 182

ALSPAC AF: 0.0568 AC: 219

ESP6500AA AF: 0.00795 AC: 35

ESP6500EA AF: 0.0531 AC: 456

ExAC AF: 0.0350 AC: 4248

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0551

EpiControl AF: 0.0511

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FOLR3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.28	T
REVEL	Benign	0.18
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.23, 0.14
ClinPred		0.0085	T
GERP RS		-1.2
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61734430; hg19: chr11-71850130;