rs530413587

Variant names:

• chr9-109167201-C-T
• rs530413587
• NM_014334.4:c.-63G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_014334.4(FRRS1L):​c.-63G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,255,274 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: FRRS1L NM_014334.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.278
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071451664).
• BP6: Variant 9-109167201-C-T is Benign according to our data. Variant chr9-109167201-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542875.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00286 (428/149680) while in subpopulation AFR AF = 0.00974 (401/41182). AF 95% confidence interval is 0.00895. There are 0 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

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.-63G>A		5_prime_UTR	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.-63G>A		5_prime_UTR	Exon 1 of 5	ENSP00000477141.2
	FRRS1L	ENST00000644747.1		n.-198G>A		upstream_gene	N/A	ENSP00000493964.1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 428 AN: 149572 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00977

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

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: 0.00

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.00 AC: 0 AN: 12496 AF XY: 0.00

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: 0.000262 AC: 290 AN: 1105594 Hom.: 0 Cov.: 31 AF XY: 0.000260 AC XY: 139 AN XY: 534466

African (AFR) AF: 0.0119 AC: 260 AN: 21790

American (AMR) AF: 0.000465 AC: 5 AN: 10742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13650

East Asian (EAS) AF: 0.00 AC: 0 AN: 22232

South Asian (SAS) AF: 0.0000260 AC: 1 AN: 38414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2848

European-Non Finnish (NFE) AF: 0.00000322 AC: 3 AN: 930530

Other (OTH) AF: 0.000491 AC: 21 AN: 42774

GnomAD4 genome AF: 0.00286 AC: 428 AN: 149680 Hom.: 0 Cov.: 28 AF XY: 0.00272 AC XY: 199 AN XY: 73038

African (AFR) AF: 0.00974 AC: 401 AN: 41182

American (AMR) AF: 0.00159 AC: 24 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 4950

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67106

Other (OTH) AF: 0.00144 AC: 3 AN: 2080

Alfa AF: 0.00215 Hom.: 0

ExAC AF: 0.000147 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Developmental and epileptic encephalopathy, 37 (1)
-	-	1	FRRS1L-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.28
PrimateAI	Pathogenic	0.87	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.072
MVP		0.25
MPC		0.080
ClinPred		0.30	T
GERP RS		0.42
PromoterAI		-0.13	Neutral
Varity_R		0.057
gMVP		0.095
Mutation Taster		=100/0	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: rs530413587; hg19: chr9-111929481; COSMIC: COSV65804059; COSMIC: COSV65804059;