chr1-35893694-CCTT-C

Variant names:

• chr1-35893694-CCTT-C
• rs1553154062
• NM_012199.5:c.539_541delTCT

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

AGO1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 521576.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012199.5. 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
	AGO1	NM_012199.5	MANE Select	c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	Exon 5 of 19	NP_036331.1	Q9UL18
	AGO1	NM_001317122.2		c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	Exon 5 of 19	NP_001304051.1	A0A6I8PTZ8
	AGO1	NM_001317123.2		c.314_316delTCT	p.Phe105del	disruptive_inframe_deletion	Exon 5 of 19	NP_001304052.1	Q5TA58

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGO1	ENST00000373204.6	TSL:1 MANE Select	c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	Exon 5 of 19	ENSP00000362300.4	Q9UL18
	AGO1	ENST00000674426.1		c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	Exon 5 of 19	ENSP00000501372.1	A0A6I8PTZ8
	AGO1	ENST00000931711.1		c.539_541delTCT	p.Phe180del	disruptive_inframe_deletion	Exon 5 of 19	ENSP00000601770.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	not provided (4)
3	-	-	Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental abnormality (1)
1	-	-	See cases (1)
1	-	-	Seizure;C0036857:Severe intellectual disability;C0040822:Tremor;C0085271:Self-injurious behavior;C1837397:Severe global developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs1553154062; hg19: chr1-36359295; COSMIC: COSV106533420;