1-35893682-C-T

Variant names:

• chr1-35893682-C-T
• NM_012199.5:c.521C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_012199.5(AGO1):​c.521C>T​(p.Pro174Leu) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGO1 NM_012199.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 5.6761 (above the threshold of 3.09). Trascript score misZ: 6.4282 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures.

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.521C>T	p.Pro174Leu	missense	Exon 5 of 19	NP_036331.1	Q9UL18
	AGO1	NM_001317122.2		c.521C>T	p.Pro174Leu	missense	Exon 5 of 19	NP_001304051.1	A0A6I8PTZ8
	AGO1	NM_001317123.2		c.296C>T	p.Pro99Leu	missense	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.521C>T	p.Pro174Leu	missense	Exon 5 of 19	ENSP00000362300.4	Q9UL18
	AGO1	ENST00000674426.1		c.521C>T	p.Pro174Leu	missense	Exon 5 of 19	ENSP00000501372.1	A0A6I8PTZ8
	AGO1	ENST00000931711.1		c.521C>T	p.Pro174Leu	missense	Exon 5 of 19	ENSP00000601770.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0080	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.43
Sift	Benign	0.034	D
Sift4G	Uncertain	0.040	D
Polyphen		0.98	D
Vest4		0.52
MutPred		0.63		Loss of phosphorylation at T173 (P = 0.0579)
MVP		0.80
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.55
gMVP		0.97
Mutation Taster		=17/83	disease causing

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

hg19: chr1-36359283;