chr1-35893694-CCTT-C

Position:

• chr1-35893694-CCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_012199.5(AGO1):​c.539_541delTCT​(p.Phe180del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGO1 NM_012199.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:2
• Conservation: PhyloP100: 7.82

Genes affected

AGO1 (HGNC:3262): (argonaute RISC component 1) This gene encodes a member of the argonaute family of proteins, which associate with small RNAs and have important roles in RNA interference (RNAi) and RNA silencing. This protein binds to microRNAs (miRNAs) or small interfering RNAs (siRNAs) and represses translation of mRNAs that are complementary to them. It is also involved in transcriptional gene silencing (TGS) of promoter regions that are complementary to bound short antigene RNAs (agRNAs), as well as in the degradation of miRNA-bound mRNA targets. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A recent study showed this gene to be an authentic stop codon readthrough target, and that its mRNA could give rise to an additional C-terminally extended isoform by use of an alternative in-frame translation termination codon. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_012199.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-35893694-CCTT-C is Pathogenic according to our data. Variant chr1-35893694-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521576.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGO1	NM_012199.5	c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	5/19	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	5/19		NP_001304051.1
AGO1	NM_001317123.2	c.314_316delTCT	p.Phe105del	disruptive_inframe_deletion	5/19		NP_001304052.1
AGO1	XM_011541236.3	c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	5/19		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	5/19	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Aug 03, 2017	This 10 year old male has a history of autism spectrum disorder, epilepsy, growth hormone deficiency, hypothyroidism, and ADHD combined type. Patient has had multiple EEGs that reportedly showed centrotemporal spikes that were considered epileptiform, though no seizures have been noted. He has reportedly had two normal MRIs. He is heterozygous for a de novo variant (c.539_541delTCT) in AGO1, which causes an in-frame deletion of one amino acid, phenylalanine 180. This variant is absent from gnomAD. This is a gene of uncertain significance; no known human disorders have been clearly associated with this gene. He is also heterozygous for a nonsense POLG variant that was paternally inherited. His father is reportedly unaffected. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2024	In-frame deletion of one amino acid in a non-repeat region; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35060114, 34930816) -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 17, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -

Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. This gene is associated with neurodevelopmental disorder with language delay and behavioural abnormalities, with or without seizures (MIM#620292). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated argonaute linker 1 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. ClinVar also contains some older entries with VUS classifications. This variant has also been reported in six unrelated de novo individuals with neurodevelopmental disorder with intellectual disability, with four individuals also having seizures (PMID: 35060114, 34930816, 36563181). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jan 02, 2025	- -

Neurodevelopmental abnormality Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

May 15, 2020

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The c.539_541delTCT (p.F180del) alteration, located in coding exon 5 of the AGO1 gene, results from an in-frame TCT deletion at nucleotide positions c.539 to c.541. This results in the deletion of a phenylalanine residue at codon 180. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.F180 amino acid is located in the L1 linker domain, which connects the N-terminal and PAZ domains (Yuan, 2005). The L1 linker domain has been shown to interact with the DNA heteroduplex, guide RNA strands, and complementary DNA target strands (Miyoshi, 2016). Interactions between the L1 linker and the DNA target strand play an important role in DNA silencing activity (Miyoshi, 2016). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PM2_supporting;PM4_moderate;PM6_moderate;PP3_supporting -

Seizure;C0036857:Intellectual disability, severe;C0040822:Tremor;C0085271:Self-injurious behavior;C1837397:Severe global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Sep 07, 2022

_x000D_ Criteria applied: PS2, PS4_MOD, PM1, PM2_SUP, PM4_SUP -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553154062; hg19: chr1-36359295;