dbSNP rs369193985: FRRS1L:p.Arg252Leu (chr9-109137582-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.755G>T(p.Arg252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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. R252H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FRRS1L
NM_014334.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.51

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:

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=0.37346363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRRS1L	NM_014334.4 link	c.755G>T	p.Arg252Leu	missense_variant	Exon 5 of 5	ENST00000561981.5	NP_055149.3	Q9P0K9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRRS1L	ENST00000561981.5 link	c.755G>T	p.Arg252Leu	missense_variant	Exon 5 of 5	1	NM_014334.4	ENSP00000477141.2		Q9P0K9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459342

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726006

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

85890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110300

Other (OTH)

AF:

0.00

AC:

AN:

60282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.0031

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0080

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

1.5

PrimateAI

Benign

0.48

Sift4G

Uncertain

0.0080

Polyphen

0.96

Vest4

0.51

MutPred

0.51

Loss of disorder (P = 0.0306);

MVP

0.52

MPC

0.19

ClinPred

0.96

GERP RS

5.0

Varity_R

0.37

gMVP

0.73

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over