rs74665168

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-35888584-G-A
• chr1-35888584-G-C
• chr1-35888584-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012199.5(AGO1):​c.183G>A​(p.Pro61Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,614,128 control chromosomes in the GnomAD database, including 19 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 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (17 hom.)
• Consequence: AGO1 NM_012199.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.21
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-35888584-G-A is Benign according to our data. Variant chr1-35888584-G-A is described in ClinVar as Benign. ClinVar VariationId is 791606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000742 (1084/1461860) while in subpopulation AMR AF = 0.0205 (918/44724). AF 95% confidence interval is 0.0194. There are 17 homozygotes in GnomAdExome4. There are 463 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 194 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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152150 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00305 AC: 767 AN: 251316 AF XY: 0.00236

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000742 AC: 1084 AN: 1461860 Hom.: 17 Cov.: 31 AF XY: 0.000637 AC XY: 463 AN XY: 727230

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0205 AC: 918 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000731 AC: 29 AN: 39698

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000674 AC: 75 AN: 1112000

Other (OTH) AF: 0.000596 AC: 36 AN: 60394

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152268 Hom.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74456

African (AFR) AF: 0.000578 AC: 24 AN: 41546

American (AMR) AF: 0.0105 AC: 160 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.00235

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	AGO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.5
DANN	Benign	0.70
PhyloP100		-5.2
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74665168; hg19: chr1-36354185;