Genetic Variant AGO1:p.Pro61Pro (chr1-35888584-G-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -5.21

Publications

2 publications found

Variant links:

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)

AGO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1212 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGO1	NM_012199.5	MANE Select	c.183G>C	p.Pro61Pro	synonymous	Exon 2 of 19	NP_036331.1	Q9UL18
AGO1	NM_001317122.2		c.183G>C	p.Pro61Pro	synonymous	Exon 2 of 19	NP_001304051.1	A0A6I8PTZ8
AGO1	NM_001317123.2		c.-43G>C		5_prime_UTR	Exon 2 of 19	NP_001304052.1	Q5TA58

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGO1	ENST00000373204.6	TSL:1 MANE Select	c.183G>C	p.Pro61Pro	synonymous	Exon 2 of 19	ENSP00000362300.4	Q9UL18
AGO1	ENST00000674426.1		c.183G>C	p.Pro61Pro	synonymous	Exon 2 of 19	ENSP00000501372.1	A0A6I8PTZ8
AGO1	ENST00000931711.1		c.183G>C	p.Pro61Pro	synonymous	Exon 2 of 19	ENSP00000601770.1

Frequencies

GnomAD3 genomes

AF:

0.00795

AC:

1209

AN:

152150

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00214

AC:

538

AN:

251316

AF XY:

0.00166

show subpopulations

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 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.:

Cov.:

AF XY:

0.000798

AC XY:

580

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0306

AC:

1025

AN:

33478

American (AMR)

AF:

0.00103

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000378

AC:

AN:

39698

South Asian (SAS)

AF:

0.000997

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112000

Other (OTH)

AF:

0.00233

AC:

141

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00796

AC:

1212

AN:

152268

Hom.:

Cov.:

AF XY:

0.00727

AC XY:

541

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0274

AC:

1137

AN:

41546

American (AMR)

AF:

0.00281

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00154

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.00891

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

AGO1-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.60

(source)

DANN

Benign

0.63

PhyloP100

-5.2

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over