11-72139407-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000804.4(FOLR3):c.418G>A(p.Glu140Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. E140E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOLR3 NM_000804.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.104

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14375564).
• BP6: Variant 11-72139407-G-A is Benign according to our data. Variant chr11-72139407-G-A is described in ClinVar as [Benign]. Clinvar id is 3053064.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOLR3	NM_000804.4	c.418G>A	p.Glu140Lys	missense_variant	4/5	ENST00000611028.3
FOLR3	NR_178088.1	n.596G>A		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOLR3	ENST00000611028.3	c.418G>A	p.Glu140Lys	missense_variant	4/5	1	NM_000804.4	P1
FOLR3	ENST00000612844.4	c.*27G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	1
FOLR3	ENST00000622388.4	c.418G>A	p.Glu140Lys	missense_variant	5/6	5
FOLR3	ENST00000545379.1	n.158G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FOLR3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 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	0.10
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.19	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.10	T;T
Vest4		0.36
MVP		0.048
ClinPred		0.62	D
GERP RS		-2.0
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1422084123; hg19: chr11-71850451;