rs6875787

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_020227.4(PRDM9):c.2042C>G(p.Thr681Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.74 ( 8722 hom., cov: 6)

Exomes 𝑓: 0.77 ( 102722 hom. )

Failed GnomAD Quality Control

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -15.7

Variant links:

Genes affected

PRDM9 (HGNC:13994): (PR/SET domain 9) The protein encoded by this gene is a zinc finger protein with histone methyltransferase activity that catalyzes histone H3 lysine 4 trimethylation (H3K4me3) during meiotic prophase. This protein contains multiple domains, including a Kruppel-associated box (KRAB) domain, an SSX repression domain (SSXRD), a PRD1-BF1 and RIZ homologous region, a subclass of SET (PR/SET) domain, and a tandem array of C2H2 zinc fingers. The zinc finger array recognizes a short sequence motif, leading to local H3K4me3, and meiotic recombination hotspot activity. The observed allelic variation alters the DNA-binding sequence specificity of the protein, resulting in distinct meiotic recombination hotspots amongst individuals and populations. Multiple alternate alleles of this gene have been described. [provided by RefSeq, Jul 2015]

PRDM9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.4098835E-4).

BP6

Variant 5-23527130-C-G is Benign according to our data. Variant chr5-23527130-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 436411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM9	NM_020227.4 linkuse as main transcript	c.2042C>G	p.Thr681Ser	missense_variant	11/11	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 linkuse as main transcript	c.2042C>G	p.Thr681Ser	missense_variant	11/11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4 linkuse as main transcript	c.2042C>G	p.Thr681Ser	missense_variant	11/11	1	NM_020227.4	ENSP00000296682.4		Q9NQV7
PRDM9	ENST00000502755.6 linkuse as main transcript	c.2042C>G	p.Thr681Ser	missense_variant	11/11	4		ENSP00000425471.2		Q9NQV7D6RD68

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

23756

AN:

31880

Hom.:

8732

Cov.:

FAILED QC

Gnomad AFR

AF:

0.541

Gnomad AMI

AF:

0.750

Gnomad AMR

AF:

0.773

Gnomad ASJ

AF:

0.811

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.776

Gnomad FIN

AF:

0.823

Gnomad MID

AF:

0.857

Gnomad NFE

AF:

0.825

Gnomad OTH

AF:

0.761

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.766

AC:

284301

AN:

370918

Hom.:

102722

Cov.:

AF XY:

0.773

AC XY:

154247

AN XY:

199466

show subpopulations

Gnomad4 AFR exome

AF:

0.560

Gnomad4 AMR exome

AF:

0.698

Gnomad4 ASJ exome

AF:

0.747

Gnomad4 EAS exome

AF:

0.593

Gnomad4 SAS exome

AF:

0.807

Gnomad4 FIN exome

AF:

0.871

Gnomad4 NFE exome

AF:

0.780

Gnomad4 OTH exome

AF:

0.733

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.745

AC:

23745

AN:

31888

Hom.:

8722

Cov.:

AF XY:

0.748

AC XY:

12168

AN XY:

16278

show subpopulations

Gnomad4 AFR

AF:

0.540

Gnomad4 AMR

AF:

0.773

Gnomad4 ASJ

AF:

0.811

Gnomad4 EAS

AF:

0.645

Gnomad4 SAS

AF:

0.773

Gnomad4 FIN

AF:

0.823

Gnomad4 NFE

AF:

0.825

Gnomad4 OTH

AF:

0.758

ExAC

AF:

0.213

AC:

5702

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 20044539, 22291443, 20818382) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0010

DANN

Benign

0.23

DEOGEN2

Benign

0.027

Eigen

Benign

-3.0

Eigen_PC

Benign

-3.1

FATHMM_MKL

Benign

0.00079

LIST_S2

Benign

0.0080

MetaRNN

Benign

0.00064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.63

PrimateAI

Benign

0.40

PROVEAN

Benign

0.030

REVEL

Benign

0.0060

Sift

Benign

0.99

Sift4G

Benign

0.87

Polyphen

0.0010

Vest4

0.0030

MutPred

0.38

Loss of phosphorylation at T681 (P = 0.0394);

MPC

0.11

ClinPred

0.043

GERP RS

-5.3

Varity_R

0.022

gMVP

0.018

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over