chr1-35897874-G-A

Variant names:

• chr1-35897874-G-A
• rs636832
• NM_012199.5:c.1020+2605G>A

Variant summary

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

The NM_012199.5(AGO1):​c.1020+2605G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,098 control chromosomes in the GnomAD database, including 6,863 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 0.23 (6863 hom., cov: 32)
• Consequence: AGO1 NM_012199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400
• Publications: 55 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.1020+2605G>A		intron_variant	Intron 8 of 18	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.1020+2605G>A		intron_variant	Intron 8 of 18		NP_001304051.1
AGO1	NM_001317123.2	c.795+2605G>A		intron_variant	Intron 8 of 18		NP_001304052.1
AGO1	XM_011541236.3	c.1020+2605G>A		intron_variant	Intron 8 of 18		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.1020+2605G>A		intron_variant	Intron 8 of 18	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35496 AN: 151980 Hom.: 6827 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0771

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.234 AC: 35591 AN: 152098 Hom.: 6863 Cov.: 32 AF XY: 0.239 AC XY: 17779 AN XY: 74352

African (AFR) AF: 0.453 AC: 18782 AN: 41454

American (AMR) AF: 0.322 AC: 4926 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 449 AN: 3472

East Asian (EAS) AF: 0.691 AC: 3581 AN: 5180

South Asian (SAS) AF: 0.160 AC: 769 AN: 4820

European-Finnish (FIN) AF: 0.128 AC: 1348 AN: 10570

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0771 AC: 5246 AN: 68006

Other (OTH) AF: 0.216 AC: 456 AN: 2114

Alfa AF: 0.143 Hom.: 8278

Bravo AF: 0.265

Asia WGS AF: 0.383 AC: 1328 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		0.040
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: rs636832; hg19: chr1-36363475;