1-35945708-G-C

Position:

• chr1-35945708-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024852.4(AGO3):​c.36G>C​(p.Gln12His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGO3 NM_024852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

Genes affected

AGO3 (HGNC:18421): (argonaute RISC catalytic component 3) This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, contains a PAZ domain and a PIWI domain, and may play a role in short-interfering-RNA-mediated gene silencing. This gene is located on chromosome 1 in a tandem cluster of closely related family members including argonaute 4 and eukaryotic translation initiation factor 2C, 1. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29558122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGO3	NM_024852.4	c.36G>C	p.Gln12His	missense_variant	2/19	ENST00000373191.9	NP_079128.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGO3	ENST00000373191.9	c.36G>C	p.Gln12His	missense_variant	2/19	2	NM_024852.4	ENSP00000362287.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.36G>C (p.Q12H) alteration is located in exon 2 (coding exon 2) of the AGO3 gene. This alteration results from a G to C substitution at nucleotide position 36, causing the glutamine (Q) at amino acid position 12 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.011	D;T;D
Sift4G	Benign	0.079	T;T;T
Polyphen		0.84	P;P;P
Vest4		0.48
MutPred		0.38		Loss of catalytic residue at Q12 (P = 0.0489);Loss of catalytic residue at Q12 (P = 0.0489);Loss of catalytic residue at Q12 (P = 0.0489);
MVP		0.26
MPC		0.56
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.25
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-36411309;