rs573029562

Positions:

• chr9-109167006-G-A
• chr9-109167006-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014334.4(FRRS1L):​c.133C>T​(p.Arg45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000651 in 1,229,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: FRRS1L NM_014334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10410631).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRRS1L	NM_014334.4	c.133C>T	p.Arg45Cys	missense_variant	1/5	ENST00000561981.5	NP_055149.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRRS1L	ENST00000561981.5	c.133C>T	p.Arg45Cys	missense_variant	1/5	1	NM_014334.4	ENSP00000477141.2
FRRS1L	ENST00000644747.1	n.-3C>T		upstream_gene_variant				ENSP00000493964.1

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149136 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000555 AC: 6 AN: 1080422 Hom.: 0 Cov.: 33 AF XY: 0.00000194 AC XY: 1 AN XY: 514696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000652

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149136 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 72690

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.94	D
Sift4G	Benign	0.080	T
Polyphen		0.0020	B
Vest4		0.32
MutPred		0.23		Loss of methylation at R96 (P = 0.0033);
MVP		0.20
MPC		0.12
ClinPred		0.35	T
GERP RS		0.59
Varity_R		0.16
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs573029562; hg19: chr9-111929286;