NM_014334.4:c.808C>T

Variant names:

• chr9-109137529-G-A
• rs878853280
• NM_014334.4:c.808C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_014334.4(FRRS1L):​c.808C>T​(p.Gln270*) variant causes a stop gained 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRRS1L NM_014334.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.60

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0839 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-109137529-G-A is Pathogenic according to our data. Variant chr9-109137529-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-109137529-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRRS1L	NM_014334.4	c.808C>T	p.Gln270*	stop_gained	Exon 5 of 5	ENST00000561981.5	NP_055149.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRRS1L	ENST00000561981.5	c.808C>T	p.Gln270*	stop_gained	Exon 5 of 5	1	NM_014334.4	ENSP00000477141.2
FRRS1L	ENST00000644747.1	n.*426C>T		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000493964.1
FRRS1L	ENST00000644747.1	n.*426C>T		3_prime_UTR_variant	Exon 4 of 4			ENSP00000493964.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 37 Pathogenic:4

Aug 05, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chorea;C0036572:Seizure;C1838578:Progressive encephalopathy Pathogenic:1

Nov 11, 2015

Kruer lab, Phoenix Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Leads to loss of protein by immunoblot; leads to impaired co-localization with GluR1 component of AMPA receptor by TIRF; loss of FRRS1L leads to attenuated AMPA currents by electrophysiology -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.30
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs878853280; hg19: chr9-111899809; COSMIC: COSV73746916; COSMIC: COSV73746916;