NM_012199.5:c.1833+258T>C

Variant names:

• chr1-35914532-T-C
• rs595055
• NM_012199.5:c.1833+258T>C

Variant summary

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

The NM_012199.5(AGO1):​c.1833+258T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,126 control chromosomes in the GnomAD database, including 13,403 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 0.34 (13403 hom., cov: 32)
• Consequence: AGO1 NM_012199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

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.1833+258T>C		intron	N/A	NP_036331.1	Q9UL18
	AGO1	NM_001317122.2		c.1833+258T>C		intron	N/A	NP_001304051.1	A0A6I8PTZ8
	AGO1	NM_001317123.2		c.1608+258T>C		intron	N/A	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.1833+258T>C		intron	N/A	ENSP00000362300.4	Q9UL18
	AGO1	ENST00000674426.1		c.1833+258T>C		intron	N/A	ENSP00000501372.1	A0A6I8PTZ8
	AGO1	ENST00000931711.1		c.1833+258T>C		intron	N/A	ENSP00000601770.1

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51725 AN: 152008 Hom.: 13360 Cov.: 32

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.341 AC: 51836 AN: 152126 Hom.: 13403 Cov.: 32 AF XY: 0.346 AC XY: 25707 AN XY: 74376

African (AFR) AF: 0.666 AC: 27640 AN: 41482

American (AMR) AF: 0.383 AC: 5856 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 738 AN: 3468

East Asian (EAS) AF: 0.792 AC: 4098 AN: 5176

South Asian (SAS) AF: 0.320 AC: 1544 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1917 AN: 10568

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9181 AN: 68006

Other (OTH) AF: 0.314 AC: 663 AN: 2112

Alfa AF: 0.190 Hom.: 6336

Bravo AF: 0.374

Asia WGS AF: 0.523 AC: 1813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.16
DANN	Benign	0.60
PhyloP100		-2.4
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: rs595055; hg19: chr1-36380133;