rs936685159

chr9-109166949-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014334.4(FRRS1L):c.190G>C(p.Gly64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,363,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G64D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: FRRS1L NM_014334.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRRS1L	NM_014334.4	c.190G>C	p.Gly64Arg	missense_variant	1/5	ENST00000561981.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRRS1L	ENST00000561981.5	c.190G>C	p.Gly64Arg	missense_variant	1/5	1	NM_014334.4	P1
FRRS1L	ENST00000644747.1	c.55G>C	p.Gly19Arg	missense_variant, NMD_transcript_variant	1/4
FRRS1L	ENST00000642299.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000400 AC: 6 AN: 150056 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000659 AC: 8 AN: 1213280 Hom.: 0 Cov.: 33 AF XY: 0.00000507 AC XY: 3 AN XY: 592208

Gnomad4 AFR exome AF: 0.000154

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000204

Gnomad4 OTH exome AF: 0.0000411

GnomAD4 genome AF: 0.0000400 AC: 6 AN: 150162 Hom.: 0 Cov.: 25 AF XY: 0.0000409 AC XY: 3 AN XY: 73298

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 37 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 13, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 115 of the FRRS1L protein (p.Gly115Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FRRS1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 542866). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.76	D
PrimateAI	Pathogenic	0.97	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.14		Gain of phosphorylation at S113 (P = 0.1077);
MVP		0.50
MPC		0.18
ClinPred		0.45	T
GERP RS		2.6
Varity_R		0.23
gMVP		0.54

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: rs936685159; hg19: chr9-111929229;