NM_014334.4:c.-122C>G

Variant names:

• chr9-109167260-G-C
• rs560644274
• NM_014334.4:c.-122C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014334.4(FRRS1L):​c.-122C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FRRS1L NM_014334.4 upstream_gene
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.16
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0098873675).

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.-122C>G		upstream_gene	N/A	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.-122C>G		upstream_gene	N/A	ENSP00000477141.2	Q9P0K9

Frequencies

GnomAD3 genomes AF: 0.000518 AC: 78 AN: 150650 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

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: 0.000482

GnomAD2 exomes AF: 0.0000129 AC: 1 AN: 77634 AF XY: 0.0000229

Gnomad AFR exome AF: 0.000412

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000201 AC: 25 AN: 1245414 Hom.: 0 Cov.: 25 AF XY: 0.0000196 AC XY: 12 AN XY: 612886

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

African (AFR) AF: 0.000771 AC: 20 AN: 25934

American (AMR) AF: 0.0000787 AC: 2 AN: 25422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19794

East Asian (EAS) AF: 0.00 AC: 0 AN: 27284

South Asian (SAS) AF: 0.00 AC: 0 AN: 61566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1002142

Other (OTH) AF: 0.0000600 AC: 3 AN: 50006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000156541), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000517 AC: 78 AN: 150766 Hom.: 0 Cov.: 28 AF XY: 0.000611 AC XY: 45 AN XY: 73606

African (AFR) AF: 0.00172 AC: 71 AN: 41300

American (AMR) AF: 0.000395 AC: 6 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 4952

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67494

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000281 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Developmental and epileptic encephalopathy, 37 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.87	D
Sift4G	Benign	0.24	T
Polyphen		0.98	D
Vest4		0.28
MutPred		0.19		Loss of glycosylation at S14 (P = 0.2176)
MVP		0.63
MPC		0.083
ClinPred		0.57	D
GERP RS		2.1
PromoterAI		0.30	Neutral
Varity_R		0.12
gMVP		0.094

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: rs560644274; hg19: chr9-111929540;