11-72139116-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000804.4(FOLR3):c.324G>C(p.Glu108Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,886 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E108Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0065 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (12 hom.)
• Consequence: FOLR3 NM_000804.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.83

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011602581).
• BP6: Variant 11-72139116-G-C is Benign according to our data. Variant chr11-72139116-G-C is described in ClinVar as [Benign]. Clinvar id is 711557.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00648 (987/152330) while in subpopulation AFR AF= 0.0223 (925/41566). AF 95% confidence interval is 0.0211. There are 15 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOLR3	NM_000804.4	c.324G>C	p.Glu108Asp	missense_variant	3/5	ENST00000611028.3
FOLR3	NR_178088.1	n.502G>C		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOLR3	ENST00000611028.3	c.324G>C	p.Glu108Asp	missense_variant	3/5	1	NM_000804.4	P1
FOLR3	ENST00000612844.4	c.452G>C	p.Ser151Thr	missense_variant, NMD_transcript_variant	3/5	1
FOLR3	ENST00000622388.4	c.324G>C	p.Glu108Asp	missense_variant	4/6	5

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 983 AN: 152212 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00159 AC: 397 AN: 250462 Hom.: 3 AF XY: 0.00122 AC XY: 165 AN XY: 135496

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000663 AC: 969 AN: 1461556 Hom.: 12 Cov.: 34 AF XY: 0.000565 AC XY: 411 AN XY: 727064

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152330 Hom.: 15 Cov.: 32 AF XY: 0.00619 AC XY: 461 AN XY: 74492

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00183 Hom.: 2

Bravo AF: 0.00683

ExAC AF: 0.00191 AC: 232

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 21, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
Sift4G	Uncertain	0.0060	D;D
Vest4		0.70
MVP		0.33
ClinPred		0.027	T
GERP RS		2.3
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs188821779; hg19: chr11-71850160;