1-35888584-G-C

Variant names:

• chr1-35888584-G-C
• rs74665168
• NM_012199.5:c.183G>C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_012199.5(AGO1):​c.183G>C​(p.Pro61Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,126 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P61P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (6 hom.)
• Consequence: AGO1 NM_012199.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -5.21

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-35888584-G-C is Benign according to our data. Variant chr1-35888584-G-C is described in ClinVar as [Benign]. Clinvar id is 720251.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00796 (1212/152268) while in subpopulation AFR AF= 0.0274 (1137/41546). AF 95% confidence interval is 0.026. There are 16 homozygotes in gnomad4. There are 541 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.183G>C	p.Pro61Pro	synonymous_variant	Exon 2 of 19	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.183G>C	p.Pro61Pro	synonymous_variant	Exon 2 of 19		NP_001304051.1
AGO1	XM_011541236.3	c.183G>C	p.Pro61Pro	synonymous_variant	Exon 2 of 19		XP_011539538.1
AGO1	NM_001317123.2	c.-43G>C		5_prime_UTR_variant	Exon 2 of 19		NP_001304052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.183G>C	p.Pro61Pro	synonymous_variant	Exon 2 of 19	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes AF: 0.00795 AC: 1209 AN: 152150 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00214 AC: 538 AN: 251316 Hom.: 6 AF XY: 0.00166 AC XY: 226 AN XY: 135828

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000906 AC: 1325 AN: 1461858 Hom.: 6 Cov.: 31 AF XY: 0.000798 AC XY: 580 AN XY: 727230

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00796 AC: 1212 AN: 152268 Hom.: 16 Cov.: 32 AF XY: 0.00727 AC XY: 541 AN XY: 74458

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.00891

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AGO1-related disorder Benign:1

Jun 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.60
DANN	Benign	0.63

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: rs74665168; hg19: chr1-36354185;