chr1-35893108-G-C

Variant names:

• chr1-35893108-G-C
• rs1479111626
• NM_012199.5:c.342G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012199.5(AGO1):​c.342G>C​(p.Glu114Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,712 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AGO1 NM_012199.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1937812).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGO1	NM_012199.5	c.342G>C	p.Glu114Asp	missense_variant	Exon 4 of 19	ENST00000373204.6	NP_036331.1
AGO1	NM_001317122.2	c.342G>C	p.Glu114Asp	missense_variant	Exon 4 of 19		NP_001304051.1
AGO1	NM_001317123.2	c.117G>C	p.Glu39Asp	missense_variant	Exon 4 of 19		NP_001304052.1
AGO1	XM_011541236.3	c.342G>C	p.Glu114Asp	missense_variant	Exon 4 of 19		XP_011539538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGO1	ENST00000373204.6	c.342G>C	p.Glu114Asp	missense_variant	Exon 4 of 19	1	NM_012199.5	ENSP00000362300.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.342G>C (p.E114D) alteration is located in exon 4 (coding exon 4) of the AGO1 gene. This alteration results from a G to C substitution at nucleotide position 342, causing the glutamic acid (E) at amino acid position 114 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.025	.;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.17
Sift	Benign	0.41	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0010	.;B
Vest4		0.47
MutPred		0.37		.;Loss of stability (P = 0.2613);
MVP		0.49
MPC		1.9
ClinPred		0.44	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1479111626; hg19: chr1-36358709;