1-35891011-G-T

Variant names:

• chr1-35891011-G-T
• rs11263833
• NM_012199.5:c.210-1546G>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.210-1546G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0868 in 152,218 control chromosomes in the GnomAD database, including 2,030 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.

• Frequency: Genomes: 𝑓 0.087 (2030 hom., cov: 32)
• Consequence: AGO1 NM_012199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.762
• Publications: 3 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: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.210-1546G>T		intron_variant	Intron 2 of 18	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.210-1546G>T		intron_variant	Intron 2 of 18		NP_001304051.1
AGO1	NM_001317123.2	c.-16-1546G>T		intron_variant	Intron 2 of 18		NP_001304052.1
AGO1	XM_011541236.3	c.210-1546G>T		intron_variant	Intron 2 of 18		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.210-1546G>T		intron_variant	Intron 2 of 18	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13173 AN: 152100 Hom.: 2021 Cov.: 32

Gnomad AFR AF: 0.0994

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.0658

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.0889

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0868 AC: 13205 AN: 152218 Hom.: 2030 Cov.: 32 AF XY: 0.0955 AC XY: 7109 AN XY: 74422

African (AFR) AF: 0.0993 AC: 4121 AN: 41510

American (AMR) AF: 0.240 AC: 3672 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.677 AC: 3504 AN: 5176

South Asian (SAS) AF: 0.0659 AC: 318 AN: 4826

European-Finnish (FIN) AF: 0.0752 AC: 798 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00764 AC: 520 AN: 68028

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

Alfa AF: 0.0375 Hom.: 766

Bravo AF: 0.107

Asia WGS AF: 0.293 AC: 1017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.62
PhyloP100		-0.76
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: rs11263833; hg19: chr1-36356612;