1-35888566-C-T

Variant names:

• chr1-35888566-C-T
• rs143228790
• NM_012199.5:c.165C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001317123.2(AGO1):​c.-61C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,206 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (76 hom.)
• Consequence: AGO1 NM_001317123.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.03

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: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-35888566-C-T is Benign according to our data. Variant chr1-35888566-C-T is described in ClinVar as [Benign]. Clinvar id is 787855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0019 (290/152314) while in subpopulation SAS AF= 0.0351 (169/4820). AF 95% confidence interval is 0.0307. There are 4 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 290 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.165C>T	p.Tyr55Tyr	synonymous_variant	Exon 2 of 19	ENST00000373204.6	NP_036331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.165C>T	p.Tyr55Tyr	synonymous_variant	Exon 2 of 19	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00536 AC: 1347 AN: 251464 Hom.: 25 AF XY: 0.00675 AC XY: 918 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0363

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00257 AC: 3758 AN: 1461892 Hom.: 76 Cov.: 31 AF XY: 0.00347 AC XY: 2523 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0347

Gnomad4 FIN exome AF: 0.00730

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00190 AC: 290 AN: 152314 Hom.: 4 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74486

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0351

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000562 Hom.: 0

Bravo AF: 0.000302

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AGO1-related disorder Benign:1

Jun 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.53

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: rs143228790; hg19: chr1-36354167; COSMIC: COSV64596491; COSMIC: COSV64596491;