chr12-130343005-T-G

Variant names:

• chr12-130343005-T-G
• rs75876550
• NM_004764.5:c.94T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004764.5(PIWIL1):​c.94T>G​(p.Tyr32Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,930 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y32C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (29 hom.)
• Consequence: PIWIL1 NM_004764.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.67
• Publications: 1 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026398003).
• BP6: Variant 12-130343005-T-G is Benign according to our data. Variant chr12-130343005-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3056689.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00973 (1482/152344) while in subpopulation AFR AF = 0.034 (1415/41576). AF 95% confidence interval is 0.0326. There are 25 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

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.94T>G	p.Tyr32Asp	missense	Exon 3 of 21	NP_004755.2	Q96J94-1
	PIWIL1	NM_001190971.2		c.94T>G	p.Tyr32Asp	missense	Exon 3 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.94T>G	p.Tyr32Asp	missense	Exon 3 of 21	ENSP00000245255.3	Q96J94-1
	PIWIL1	ENST00000542723.1	TSL:2	c.94T>G	p.Tyr32Asp	missense	Exon 2 of 4	ENSP00000438582.1	F5H2F7
	PIWIL1	ENST00000546060.5	TSL:4	c.94T>G	p.Tyr32Asp	missense	Exon 3 of 5	ENSP00000442086.1	F5H889

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1474 AN: 152226 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

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: 0.0000588

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00255 AC: 642 AN: 251442 AF XY: 0.00176

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000991 AC: 1448 AN: 1461586 Hom.: 29 Cov.: 31 AF XY: 0.000884 AC XY: 643 AN XY: 727110

African (AFR) AF: 0.0360 AC: 1205 AN: 33454

American (AMR) AF: 0.00165 AC: 74 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111768

Other (OTH) AF: 0.00215 AC: 130 AN: 60384

GnomAD4 genome AF: 0.00973 AC: 1482 AN: 152344 Hom.: 25 Cov.: 33 AF XY: 0.00934 AC XY: 696 AN XY: 74494

African (AFR) AF: 0.0340 AC: 1415 AN: 41576

American (AMR) AF: 0.00314 AC: 48 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00388 Hom.: 21

Bravo AF: 0.0113

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00310 AC: 376

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PIWIL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.33	N
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.051
Sift	Benign	0.20	T
Sift4G	Benign	0.63	T
Polyphen		0.62	P
Vest4		0.42
MVP		0.53
MPC		1.9
ClinPred		0.013	T
GERP RS		3.9
Varity_R		0.083
gMVP		0.43
Mutation Taster		=97/3	polymorphism

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: rs75876550; hg19: chr12-130827550;