chr1-35893730-T-C

Position:

• chr1-35893730-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_012199.5(AGO1):​c.569T>C​(p.Leu190Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGO1 NM_012199.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AGO1. . Gene score misZ 5.6761 (greater than the threshold 3.09). Trascript score misZ 6.4282 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 1-35893730-T-C is Pathogenic according to our data. Variant chr1-35893730-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984614.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-35893730-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGO1	NM_012199.5	c.569T>C	p.Leu190Pro	missense_variant	5/19	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.569T>C	p.Leu190Pro	missense_variant	5/19		NP_001304051.1
AGO1	NM_001317123.2	c.344T>C	p.Leu115Pro	missense_variant	5/19		NP_001304052.1
AGO1	XM_011541236.3	c.569T>C	p.Leu190Pro	missense_variant	5/19		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.569T>C	p.Leu190Pro	missense_variant	5/19	1	NM_012199.5	ENSP00000362300	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 04, 2020

- -

Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 10, 2012

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Dec 08, 2021

PM1, PS4_MOD, PP3, PP2, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.6	.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.87
MutPred		0.87		.;Gain of disorder (P = 0.0058);
MVP		0.80
MPC		3.7
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0

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: rs1645264815; hg19: chr1-36359331;