Genetic Variant FRRS1L:p.Ala46Glu (chr9-109167002-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014334.4(FRRS1L):c.137C>A(p.Ala46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000181 in 1,102,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

FRRS1L
NM_014334.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

0 publications found

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]

FRRS1L Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 37
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FRRS1L links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.122528225).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1L	NM_014334.4	MANE Select	c.137C>A	p.Ala46Glu	missense	Exon 1 of 5	NP_055149.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FRRS1L	ENST00000561981.5	TSL:1 MANE Select	c.137C>A	p.Ala46Glu	missense	Exon 1 of 5	ENSP00000477141.2
FRRS1L	ENST00000644747.1		n.2C>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000493964.1
FRRS1L	ENST00000642299.1		n.-71C>A		upstream_gene	N/A	ENSP00000495137.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000181

AC:

AN:

1102912

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

527718

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23112

American (AMR)

AF:

0.00

AC:

AN:

11112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14874

East Asian (EAS)

AF:

0.00

AC:

AN:

26022

South Asian (SAS)

AF:

0.00

AC:

AN:

26366

European-Finnish (FIN)

AF:

0.0000419

AC:

AN:

23848

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2980

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

930612

Other (OTH)

AF:

0.00

AC:

AN:

43986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.026

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.42

M_CAP

Benign

0.080

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.6

PrimateAI

Pathogenic

0.91

Sift4G

Benign

0.12

Polyphen

0.16

Vest4

0.20

MutPred

0.12

Loss of methylation at R98 (P = 0.056)

MVP

0.23

MPC

0.10

ClinPred

0.081

GERP RS

0.64

PromoterAI

0.033

Neutral

(source)

Varity_R

0.17

gMVP

0.26

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over