rs1554736531

Variant names:

• chr9-109167176-G-A
• rs1554736531
• NM_014334.4:c.-38C>T

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.-38C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,002,548 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 (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: FRRS1L NM_014334.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.916
• 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):

• 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

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=0.2350213).

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.-38C>T		5_prime_UTR	Exon 1 of 5	NP_055149.3	Q9P0K9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1L	ENST00000561981.5	TSL:1 MANE Select	c.-38C>T		5_prime_UTR	Exon 1 of 5	ENSP00000477141.2	Q9P0K9
	FRRS1L	ENST00000642299.1		n.-245C>T		upstream_gene	N/A	ENSP00000495137.1	A0A2R8Y5Y6
	FRRS1L	ENST00000644747.1		n.-173C>T		upstream_gene	N/A	ENSP00000493964.1	A0A2R8Y4E4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000199 AC: 2 AN: 1002548 Hom.: 0 Cov.: 31 AF XY: 0.00000211 AC XY: 1 AN XY: 474194

African (AFR) AF: 0.00 AC: 0 AN: 19928

American (AMR) AF: 0.00 AC: 0 AN: 5802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10512

East Asian (EAS) AF: 0.00 AC: 0 AN: 17696

South Asian (SAS) AF: 0.00 AC: 0 AN: 18936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2508

European-Non Finnish (NFE) AF: 0.00000229 AC: 2 AN: 872570

Other (OTH) AF: 0.00 AC: 0 AN: 37736

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.92
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.16
MutPred		0.22		Loss of glycosylation at P37 (P = 0.0795)
MVP		0.74
MPC		0.083
ClinPred		0.81	D
GERP RS		2.5
PromoterAI		-0.079	Neutral
Varity_R		0.034
gMVP		0.21

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: rs1554736531; hg19: chr9-111929456;