rs595961

Variant names:

• chr1-35902179-A-G
• rs595961
• NM_012199.5:c.1264-25A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-35902179-A-G
• chr1-35902179-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012199.5(AGO1):​c.1264-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,607,214 control chromosomes in the GnomAD database, including 62,328 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.37 (16625 hom., cov: 31)
  • Exomes 𝑓: 0.19 (45703 hom.)
• Consequence: AGO1 NM_012199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.694
• Publications: 41 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.1264-25A>G		intron_variant	Intron 10 of 18	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.1264-25A>G		intron_variant	Intron 10 of 18		NP_001304051.1
AGO1	NM_001317123.2	c.1039-25A>G		intron_variant	Intron 10 of 18		NP_001304052.1
AGO1	XM_011541236.3	c.1273-25A>G		intron_variant	Intron 10 of 18		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.1264-25A>G		intron_variant	Intron 10 of 18	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56255 AN: 151886 Hom.: 16560 Cov.: 31

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.336

GnomAD2 exomes AF: 0.304 AC: 74985 AN: 246664 AF XY: 0.282

Gnomad AFR exome AF: 0.781

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.193 AC: 281381 AN: 1455210 Hom.: 45703 Cov.: 32 AF XY: 0.193 AC XY: 139843 AN XY: 723186

African (AFR) AF: 0.797 AC: 26619 AN: 33380

American (AMR) AF: 0.447 AC: 19828 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5607 AN: 25630

East Asian (EAS) AF: 0.792 AC: 31343 AN: 39568

South Asian (SAS) AF: 0.296 AC: 25270 AN: 85414

European-Finnish (FIN) AF: 0.179 AC: 9547 AN: 53188

Middle Eastern (MID) AF: 0.216 AC: 1236 AN: 5722

European-Non Finnish (NFE) AF: 0.133 AC: 147279 AN: 1107922

Other (OTH) AF: 0.244 AC: 14652 AN: 60070

GnomAD4 genome AF: 0.371 AC: 56392 AN: 152004 Hom.: 16625 Cov.: 31 AF XY: 0.375 AC XY: 27895 AN XY: 74292

African (AFR) AF: 0.771 AC: 31950 AN: 41442

American (AMR) AF: 0.395 AC: 6030 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 746 AN: 3468

East Asian (EAS) AF: 0.796 AC: 4108 AN: 5162

South Asian (SAS) AF: 0.314 AC: 1515 AN: 4818

European-Finnish (FIN) AF: 0.182 AC: 1925 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9208 AN: 67944

Other (OTH) AF: 0.339 AC: 714 AN: 2106

Alfa AF: 0.217 Hom.: 19672

Bravo AF: 0.410

Asia WGS AF: 0.530 AC: 1840 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.54
PhyloP100		0.69
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs595961; hg19: chr1-36367780; COSMIC: COSV64596144;