22-24728343-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001255975.1(PIWIL3):c.1739G>A(p.Arg580His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PIWIL3 NM_001255975.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036436737).
• BP6: Variant 22-24728343-C-T is Benign according to our data. Variant chr22-24728343-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2221628.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIWIL3	NM_001255975.1	c.1739G>A	p.Arg580His	missense_variant	15/21	ENST00000616349.5
PIWIL3	NM_001008496.3	c.1766G>A	p.Arg589His	missense_variant	15/21
PIWIL3	NR_045648.1	n.2370G>A		non_coding_transcript_exon_variant	16/22
PIWIL3	NR_045649.2	n.2243G>A		non_coding_transcript_exon_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIWIL3	ENST00000616349.5	c.1739G>A	p.Arg580His	missense_variant	15/21	1	NM_001255975.1	A2
PIWIL3	ENST00000332271.9	c.1766G>A	p.Arg589His	missense_variant	15/21	1		P2
PIWIL3	ENST00000527701.6	c.*1711G>A		3_prime_UTR_variant, NMD_transcript_variant	16/22	1
PIWIL3	ENST00000533313.6	c.*1665G>A		3_prime_UTR_variant, NMD_transcript_variant	16/22	1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251456 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135898

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74442

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	11
Dann	Benign	0.84
DEOGEN2	Benign	0.012	T;T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.31	T;.;.;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.0	B;B;P;P
Vest4		0.053
MVP		0.32
MPC		0.14
ClinPred		0.10	T
GERP RS		0.39
Varity_R		0.033
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs574938118; hg19: chr22-25124310;