rs595961

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -12 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). 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/exons	MANE	Protein	UniProt
AGO1	NM_012199.5	c.1264-25A>G		intron_variant		ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.1264-25A>G		intron_variant			NP_001304051.1
AGO1	NM_001317123.2	c.1039-25A>G		intron_variant			NP_001304052.1
AGO1	XM_011541236.3	c.1273-25A>G		intron_variant			XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.1264-25A>G		intron_variant		1	NM_012199.5	ENSP00000362300	P1

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

GnomAD3 exomes AF: 0.304 AC: 74985 AN: 246664 Hom.: 18166 AF XY: 0.282 AC XY: 37616 AN XY: 133272

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 SAS exome AF: 0.300

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

Gnomad4 AFR exome AF: 0.797

Gnomad4 AMR exome AF: 0.447

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.792

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.244

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

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.796

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.182

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.339

Alfa AF: 0.188 Hom.: 5770

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
BranchPoint Hunter		3.0

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