12-130342644-C-G

Variant names:

• chr12-130342644-C-G
• rs1179866968
• NM_004764.5:c.53C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004764.5(PIWIL1):​c.53C>G​(p.Thr18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T18I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PIWIL1 NM_004764.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.774
• Publications: 0 publications found

Genes affected

PIWIL1 (HGNC:9007): (piwi like RNA-mediated gene silencing 1) This gene encodes a member of the PIWI subfamily of Argonaute proteins, evolutionarily conserved proteins containing both PAZ and Piwi motifs that play important roles in stem cell self-renewal, RNA silencing, and translational regulation in diverse organisms. The encoded protein may play a role as an intrinsic regulator of the self-renewal capacity of germline and hematopoietic stem cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10053435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004764.5. 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
	PIWIL1	NM_004764.5	MANE Select	c.53C>G	p.Thr18Arg	missense	Exon 2 of 21	NP_004755.2	Q96J94-1
	PIWIL1	NM_001190971.2		c.53C>G	p.Thr18Arg	missense	Exon 2 of 20	NP_001177900.1	Q96J94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIWIL1	ENST00000245255.7	TSL:1 MANE Select	c.53C>G	p.Thr18Arg	missense	Exon 2 of 21	ENSP00000245255.3	Q96J94-1
	PIWIL1	ENST00000542723.1	TSL:2	c.53C>G	p.Thr18Arg	missense	Exon 1 of 4	ENSP00000438582.1	F5H2F7
	PIWIL1	ENST00000546060.5	TSL:4	c.53C>G	p.Thr18Arg	missense	Exon 2 of 5	ENSP00000442086.1	F5H889

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461398 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727020

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111670

Other (OTH) AF: 0.0000331 AC: 2 AN: 60370

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.18	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.77
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.038
Sift	Benign	0.15	T
Sift4G	Benign	0.37	T
Polyphen		0.15	B
Vest4		0.29
MutPred		0.36		Gain of methylation at T18 (P = 0.0159)
MVP		0.45
MPC		0.69
ClinPred		0.12	T
GERP RS		0.24
PromoterAI		-0.041	Neutral
Varity_R		0.060
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1179866968; hg19: chr12-130827189;