Genetic Variant FOLR3:p.Glu140Glu (chr11-72139409-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000804.4(FOLR3):c.420G>A(p.Glu140Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,612,020 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 38 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 70 hom. )

Consequence

FOLR3
NM_000804.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.33

Publications

4 publications found

Variant links:

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]

FOLR3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-72139409-G-A is Benign according to our data. Variant chr11-72139409-G-A is described in ClinVar as Benign. ClinVar VariationId is 773826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.33 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00564 (859/152346) while in subpopulation AMR AF = 0.04 (613/15310). AF 95% confidence interval is 0.0374. There are 38 homozygotes in GnomAd4. There are 531 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000804.4. 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
	FOLR3	NM_000804.4	MANE Select	c.420G>A	p.Glu140Glu	synonymous	Exon 4 of 5	NP_000795.2	P41439-1
	FOLR3	NR_178088.1		n.598G>A		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOLR3	ENST00000611028.3	TSL:1 MANE Select	c.420G>A	p.Glu140Glu	synonymous	Exon 4 of 5	ENSP00000481114.1	P41439-1
FOLR3	ENST00000612844.4	TSL:1	n.*29G>A		non_coding_transcript_exon	Exon 4 of 5	ENSP00000481027.1	P41439-4
FOLR3	ENST00000612844.4	TSL:1	n.*29G>A		3_prime_UTR	Exon 4 of 5	ENSP00000481027.1	P41439-4

Frequencies

GnomAD3 genomes

AF:

0.00558

AC:

850

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0395

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.0281

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00623

AC:

1529

AN:

245516

AF XY:

0.00517

show subpopulations

Gnomad AFR exome

AF:

0.000327

Gnomad AMR exome

AF:

0.0255

Gnomad ASJ exome

AF:

0.00231

Gnomad EAS exome

AF:

0.0263

Gnomad FIN exome

AF:

0.00205

Gnomad NFE exome

AF:

0.000452

Gnomad OTH exome

AF:

0.00400

GnomAD4 exome

AF:

0.00221

AC:

3220

AN:

1459674

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1508

AN XY:

726022

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33414

American (AMR)

AF:

0.0269

AC:

1188

AN:

44236

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26072

East Asian (EAS)

AF:

0.0328

AC:

1301

AN:

39620

South Asian (SAS)

AF:

0.00163

AC:

140

AN:

86006

European-Finnish (FIN)

AF:

0.00193

AC:

103

AN:

53304

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000264

AC:

293

AN:

1110936

Other (OTH)

AF:

0.00224

AC:

135

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

181

363

544

726

907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00564

AC:

859

AN:

152346

Hom.:

Cov.:

AF XY:

0.00713

AC XY:

531

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41578

American (AMR)

AF:

0.0400

AC:

613

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.0282

AC:

146

AN:

5184

South Asian (SAS)

AF:

0.00207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68032

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.00667

Asia WGS

AF:

0.0140

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.2

(source)

DANN

Benign

0.54

PhyloP100

1.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over