chr9-109167291-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014334.4(FRRS1L):​c.-153A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000863 in 1,159,352 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: FRRS1L NM_014334.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.941
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.-153A>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.-153A>G		upstream_gene	N/A	ENSP00000477141.2	Q9P0K9

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 8.63e-7 AC: 1 AN: 1159352 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 569784

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

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

American (AMR) AF: 0.00 AC: 0 AN: 18972

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 22362

South Asian (SAS) AF: 0.00 AC: 0 AN: 55038

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2986

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 951346

Other (OTH) AF: 0.00 AC: 0 AN: 44974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.0	T
PhyloP100		0.94
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.77
MutPred		0.56		Loss of methylation at R5 (P = 0.1431)
MVP		0.32
ClinPred		0.066	T
GERP RS		-0.15
PromoterAI		-0.12	Neutral
Varity_R		0.21
gMVP		0.20

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;