9-109167006-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014334.4(FRRS1L):​c.133C>A​(p.Arg45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,229,646 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 7 hom., cov: 25)
Exomes 𝑓: 0.00033 ( 4 hom. )

Consequence

FRRS1L
NM_014334.4 missense

Scores

1
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.36
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004635483).
BP6
Variant 9-109167006-G-T is Benign according to our data. Variant chr9-109167006-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 476301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00407 (607/149224) while in subpopulation AFR AF= 0.0142 (580/40970). AF 95% confidence interval is 0.0132. There are 7 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FRRS1LNM_014334.4 linkc.133C>A p.Arg45Ser missense_variant 1/5 ENST00000561981.5 NP_055149.3 Q9P0K9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FRRS1LENST00000561981.5 linkc.133C>A p.Arg45Ser missense_variant 1/51 NM_014334.4 ENSP00000477141.2 Q9P0K9
FRRS1LENST00000644747.1 linkn.-3C>A upstream_gene_variant ENSP00000493964.1 A0A2R8Y4E4

Frequencies

GnomAD3 genomes
AF:
0.00408
AC:
608
AN:
149126
Hom.:
7
Cov.:
25
show subpopulations
Gnomad AFR
AF:
0.0142
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00126
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:
0.0000299
Gnomad OTH
AF:
0.00292
GnomAD3 exomes
AF:
0.000523
AC:
2
AN:
3826
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
2260
show subpopulations
Gnomad AFR exome
AF:
0.0161
Gnomad AMR exome
AF:
0.00165
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000334
AC:
361
AN:
1080422
Hom.:
4
Cov.:
33
AF XY:
0.000309
AC XY:
159
AN XY:
514696
show subpopulations
Gnomad4 AFR exome
AF:
0.0142
Gnomad4 AMR exome
AF:
0.000696
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:
0.0000109
Gnomad4 OTH exome
AF:
0.000655
GnomAD4 genome
AF:
0.00407
AC:
607
AN:
149224
Hom.:
7
Cov.:
25
AF XY:
0.00379
AC XY:
276
AN XY:
72804
show subpopulations
Gnomad4 AFR
AF:
0.0142
Gnomad4 AMR
AF:
0.00126
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000299
Gnomad4 OTH
AF:
0.00289
Alfa
AF:
0.000349
Hom.:
0
Bravo
AF:
0.00462

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024FRRS1L: BS1, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 15, 2021- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
FRRS1L-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 14, 2024This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Developmental and epileptic encephalopathy, 37 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.017
T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.48
T
MetaRNN
Benign
0.0046
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L
PrimateAI
Pathogenic
0.93
D
Sift4G
Benign
0.79
T
Polyphen
0.10
B
Vest4
0.36
MutPred
0.24
Loss of methylation at R96 (P = 0.0033);
MVP
0.23
MPC
0.094
ClinPred
0.0052
T
GERP RS
0.59
Varity_R
0.21
gMVP
0.39

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs573029562; hg19: chr9-111929286; API