Genetic Variant FRRS1L:p.Asp60Tyr (chr9-109166961-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014334.4(FRRS1L):c.178G>T(p.Asp60Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,194,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D60H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

FRRS1L
NM_014334.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39

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):

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

FRRS1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4219636).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1L	NM_014334.4	MANE Select	c.178G>T	p.Asp60Tyr	missense	Exon 1 of 5	NP_055149.3	Q9P0K9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FRRS1L	ENST00000561981.5	TSL:1 MANE Select	c.178G>T	p.Asp60Tyr	missense	Exon 1 of 5	ENSP00000477141.2	Q9P0K9
FRRS1L	ENST00000644747.1		n.43G>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000493964.1	A0A2R8Y4E4
FRRS1L	ENST00000642299.1		n.-30G>T		upstream_gene	N/A	ENSP00000495137.1	A0A2R8Y5Y6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000167

AC:

AN:

1194926

Hom.:

Cov.:

AF XY:

0.00000172

AC XY:

AN XY:

581432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25578

American (AMR)

AF:

0.00

AC:

AN:

21848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19968

East Asian (EAS)

AF:

0.00

AC:

AN:

27078

South Asian (SAS)

AF:

0.00

AC:

AN:

46782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3378

European-Non Finnish (NFE)

AF:

0.00000206

AC:

AN:

972328

Other (OTH)

AF:

0.00

AC:

AN:

47878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.023

Eigen

Benign

0.14

Eigen_PC

Benign

0.068

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.2

PhyloP100

3.4

PrimateAI

Pathogenic

0.97

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.41

MutPred

0.47

Gain of phosphorylation at D111 (P = 0.0545)

MVP

0.52

MPC

0.20

ClinPred

0.84

GERP RS

2.6

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.15

gMVP

0.45

Mutation Taster

=86/14

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