chr9-109167086-A-G

Variant names:

• chr9-109167086-A-G
• rs1477068520
• NM_014334.4:c.53T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014334.4(FRRS1L):​c.53T>C​(p.Leu18Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000968 in 1,033,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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. L18R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: FRRS1L NM_014334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.694
• Publications: 0 publications found

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

ACMG classification

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=0.15118644).

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.53T>C	p.Leu18Pro	missense	Exon 1 of 5	NP_055149.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1L	ENST00000561981.5	TSL:1 MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 5	ENSP00000477141.2
	FRRS1L	ENST00000642299.1		n.-155T>C		upstream_gene	N/A	ENSP00000495137.1
	FRRS1L	ENST00000644747.1		n.-83T>C		upstream_gene	N/A	ENSP00000493964.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.68e-7 AC: 1 AN: 1033144 Hom.: 0 Cov.: 33 AF XY: 0.00000202 AC XY: 1 AN XY: 494694

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

African (AFR) AF: 0.00 AC: 0 AN: 20530

American (AMR) AF: 0.00 AC: 0 AN: 8222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11676

East Asian (EAS) AF: 0.00 AC: 0 AN: 18064

South Asian (SAS) AF: 0.00 AC: 0 AN: 23744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2564

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 891156

Other (OTH) AF: 0.00 AC: 0 AN: 39178

⚠️ 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.

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.69
PrimateAI	Pathogenic	0.86	D
Sift4G	Uncertain	0.027	D
Polyphen		0.71	P
Vest4		0.25
MutPred		0.30		Loss of stability (P = 0.0032)
MVP		0.23
MPC		0.45
ClinPred		0.90	D
GERP RS		2.7
PromoterAI		-0.033	Neutral
Varity_R		0.67
gMVP		0.49
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1477068520; hg19: chr9-111929366;