NM_014334.4:c.178G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014334.4(FRRS1L):c.178G>C(p.Asp60His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,344,900 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. D60Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000028 ( 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):

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15668991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRRS1L	NM_014334.4 link	c.178G>C	p.Asp60His	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>C	p.Asp60His	missense_variant	Exon 1 of 5	1	NM_014334.4	ENSP00000477141.2	Q9P0K9
FRRS1L	ENST00000644747.1 link	n.43G>C		non_coding_transcript_exon_variant	Exon 1 of 4			ENSP00000493964.1	A0A2R8Y4E4
FRRS1L	ENST00000642299.1 link	n.-30G>C		upstream_gene_variant				ENSP00000495137.1	A0A2R8Y5Y6

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

149866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000109

AC:

AN:

64462

AF XY:

0.000188

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000285

AC:

AN:

1194926

Hom.:

Cov.:

AF XY:

0.0000396

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:

0.000369

AC:

AN:

27078

South Asian (SAS)

AF:

0.000406

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:

0.00

AC:

AN:

972328

Other (OTH)

AF:

0.000104

AC:

AN:

47878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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

AF:

0.0000467

AC:

AN:

149974

Hom.:

Cov.:

AF XY:

0.0000957

AC XY:

AN XY:

73168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41098

American (AMR)

AF:

0.00

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4966

South Asian (SAS)

AF:

0.00147

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67108

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.000130

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 37

Uncertain:1

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 111 of the FRRS1L protein (p.Asp111His). This variant is present in population databases (rs772506414, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FRRS1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 572403). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.023

Eigen

Benign

0.12

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.2

PhyloP100

3.4

PrimateAI

Pathogenic

0.97

Sift4G

Uncertain

0.027

Polyphen

1.0

Vest4

0.28

MutPred

0.41

Loss of phosphorylation at Y114 (P = 0.1212);

MVP

0.65

MPC

0.17

ClinPred

0.22

GERP RS

2.6

PromoterAI

-0.042

Neutral

(source)

Varity_R

0.15

gMVP

0.39

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over