NM_001255975.1:c.2507G>A

Variant names:

• chr22-24719587-C-T
• rs1383546384
• NM_001255975.1:c.2507G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001255975.1(PIWIL3):​c.2507G>A​(p.Gly836Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000379 in 1,582,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense, splice_region
• Scores: Splicing: ADA: 0.05511
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.05
• Publications: 0 publications found

Genes affected

PIWIL3 (HGNC:18443): (piwi like RNA-mediated gene silencing 3) This gene encodes a member of the PIWI subfamily of Argonaute family proteins. This subfamily of proteins contains a PAZ domain, found in proteins involved in RNA-mediated gene silencing, and a C-terminal Piwi domain. The encoded protein is thought to function in maintenance of germline cells. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001255975.1. 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
	PIWIL3	NM_001255975.1	MANE Select	c.2507G>A	p.Gly836Asp	missense splice_region	Exon 21 of 21	NP_001242904.1	B4DYF7
	PIWIL3	NM_001008496.3		c.2534G>A	p.Gly845Asp	missense splice_region	Exon 21 of 21	NP_001008496.2	Q7Z3Z3
	PIWIL3	NR_045648.1		n.3138G>A		splice_region non_coding_transcript_exon	Exon 22 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIWIL3	ENST00000616349.5	TSL:1 MANE Select	c.2507G>A	p.Gly836Asp	missense splice_region	Exon 21 of 21	ENSP00000479524.2	A0A8J9G8U8
	PIWIL3	ENST00000332271.9	TSL:1	c.2534G>A	p.Gly845Asp	missense splice_region	Exon 21 of 21	ENSP00000330031.5	Q7Z3Z3
	PIWIL3	ENST00000527701.6	TSL:1	n.*2479G>A		splice_region non_coding_transcript_exon	Exon 22 of 22	ENSP00000435718.2	E9PIP6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1430764 Hom.: 0 Cov.: 30 AF XY: 0.00000282 AC XY: 2 AN XY: 709866

African (AFR) AF: 0.00 AC: 0 AN: 31760

American (AMR) AF: 0.00 AC: 0 AN: 36944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24474

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 80766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1100070

Other (OTH) AF: 0.00 AC: 0 AN: 58978

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0035	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.84		Loss of sheet (P = 0.0817)
MVP		0.59
MPC		0.48
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.61
gMVP		0.63
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.055
dbscSNV1_RF	Benign	0.27
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

Other links and lift over

dbSNP: rs1383546384; hg19: chr22-25115554;