rs574642289

Positions:

• chr9-109141450-C-A
• chr9-109141450-C-G
• chr9-109141450-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000561981.5(FRRS1L):​c.602G>T​(p.Arg201Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRRS1L ENST00000561981.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

FRRS1L (HGNC:1362): (ferric chelate reductase 1 like) This gene encodes a component of the outer-core of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor protein in the brain. The encoded protein is thought to interact with inner-core components of the receptor, and play a role in the modulation of glutamate signaling. Mutations in this gene are associated with early infantile epileptic encephalopathy 37. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRRS1L	NM_014334.4	c.602G>T	p.Arg201Leu	missense_variant	4/5	ENST00000561981.5	NP_055149.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRRS1L	ENST00000561981.5	c.602G>T	p.Arg201Leu	missense_variant	4/5	1	NM_014334.4	ENSP00000477141	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 37 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FRRS1L-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 252 of the FRRS1L protein (p.Arg252Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.76	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.58		Loss of MoRF binding (P = 0.0372);
MVP		0.56
MPC		0.50
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.77

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: rs574642289; hg19: chr9-111903730;