dbSNP rs772506414: 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

Not reported in ClinVar

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):

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=0.4219636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRRS1L	NM_014334.4 link	c.178G>T	p.Asp60Tyr	missense_variant	Exon 1 of 5	ENST00000561981.5	NP_055149.3	Q9P0K9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FRRS1L	ENST00000561981.5 link	c.178G>T	p.Asp60Tyr	missense_variant	Exon 1 of 5	1	NM_014334.4	ENSP00000477141.2	Q9P0K9
FRRS1L	ENST00000644747.1 link	n.43G>T		non_coding_transcript_exon_variant	Exon 1 of 4			ENSP00000493964.1	A0A2R8Y4E4
FRRS1L	ENST00000642299.1 link	n.-30G>T		upstream_gene_variant				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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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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