chr1-35893691-G-A

Variant names:

• chr1-35893691-G-A
• NM_012199.5:c.530G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012199.5(AGO1):​c.530G>A​(p.Arg177His) 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 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: 9.76

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.530G>A	p.Arg177His	missense_variant	Exon 5 of 19	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.530G>A	p.Arg177His	missense_variant	Exon 5 of 19		NP_001304051.1
AGO1	NM_001317123.2	c.305G>A	p.Arg102His	missense_variant	Exon 5 of 19		NP_001304052.1
AGO1	XM_011541236.3	c.530G>A	p.Arg177His	missense_variant	Exon 5 of 19		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.530G>A	p.Arg177His	missense_variant	Exon 5 of 19	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.530G>A (p.R177H) alteration is located in exon 5 (coding exon 5) of the AGO1 gene. This alteration results from a G to A substitution at nucleotide position 530, causing the arginine (R) at amino acid position 177 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.5	.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.99	.;D
Vest4		0.68
MutPred		0.76		.;Loss of MoRF binding (P = 0.0575);
MVP		0.71
MPC		2.2
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.31
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-36359292;