chr1-35888430-C-G

Position:

• chr1-35888430-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_012199.5(AGO1):​c.29C>G​(p.Ala10Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000512 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: AGO1 NM_012199.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.94

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 -7 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AGO1. . Gene score misZ 5.6761 (greater than the threshold 3.09). Trascript score misZ 6.4282 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08979273).
• BP6: Variant 1-35888430-C-G is Benign according to our data. Variant chr1-35888430-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3257707.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGO1	NM_012199.5	c.29C>G	p.Ala10Gly	missense_variant	2/19	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.29C>G	p.Ala10Gly	missense_variant	2/19		NP_001304051.1
AGO1	XM_011541236.3	c.29C>G	p.Ala10Gly	missense_variant	2/19		XP_011539538.1
AGO1	NM_001317123.2	c.-197C>G		5_prime_UTR_variant	2/19		NP_001304052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.29C>G	p.Ala10Gly	missense_variant	2/19	1	NM_012199.5	ENSP00000362300	P1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 250796 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135508

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000536 AC: 784 AN: 1461536 Hom.: 0 Cov.: 31 AF XY: 0.000488 AC XY: 355 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000665

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74350

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

AGO1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.59	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.053
Sift	Benign	0.28	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.34
MVP		0.32
MPC		0.89
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146814747; hg19: chr1-36354031;