rs527415212

Variant names:

• chr9-109167291-T-A
• rs527415212
• NM_014334.4:c.-153A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-109167291-T-A
• chr9-109167291-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000561981.5(FRRS1L):​c.-153A>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,309,664 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00069 (4 hom., cov: 28)
  • Exomes 𝑓: 0.0012 (41 hom.)
• Consequence: FRRS1L ENST00000561981.5 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.941
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005487889).
• BP6: Variant 9-109167291-T-A is Benign according to our data. Variant chr9-109167291-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000685 (103/150334) while in subpopulation SAS AF = 0.021 (100/4762). AF 95% confidence interval is 0.0177. There are 4 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000561981.5. 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.-153A>T		upstream_gene	N/A	NP_055149.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRRS1L	ENST00000561981.5	TSL:1 MANE Select	c.-153A>T		upstream_gene	N/A	ENSP00000477141.2

Frequencies

GnomAD3 genomes AF: 0.000686 AC: 103 AN: 150234 Hom.: 4 Cov.: 28

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: 0.0210

Gnomad FIN AF: 0.0000972

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.00392 AC: 219 AN: 55826 AF XY: 0.00581

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000197

Gnomad ASJ exome AF: 0.000415

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000755

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00121 AC: 1404 AN: 1159330 Hom.: 41 Cov.: 20 AF XY: 0.00177 AC XY: 1011 AN XY: 569768

African (AFR) AF: 0.00 AC: 0 AN: 22786

American (AMR) AF: 0.000105 AC: 2 AN: 18972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15634

East Asian (EAS) AF: 0.0000447 AC: 1 AN: 22362

South Asian (SAS) AF: 0.0232 AC: 1274 AN: 55024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25254

Middle Eastern (MID) AF: 0.000335 AC: 1 AN: 2986

European-Non Finnish (NFE) AF: 0.0000589 AC: 56 AN: 951342

Other (OTH) AF: 0.00156 AC: 70 AN: 44970

GnomAD4 genome AF: 0.000685 AC: 103 AN: 150334 Hom.: 4 Cov.: 28 AF XY: 0.000994 AC XY: 73 AN XY: 73416

African (AFR) AF: 0.0000244 AC: 1 AN: 40984

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4928

South Asian (SAS) AF: 0.0210 AC: 100 AN: 4762

European-Finnish (FIN) AF: 0.0000972 AC: 1 AN: 10284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67446

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.00215 AC: 234

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.94
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.67
MutPred		0.56		Loss of methylation at R5 (P = 0.1472)
MVP		0.40
ClinPred		0.031	T
GERP RS		-0.15
PromoterAI		0.40	Neutral
Varity_R		0.24
gMVP		0.13

Splicing

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

Other links and lift over

dbSNP: rs527415212; hg19: chr9-111929571;