NM_020227.4:c.2042C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T681T) has been classified as Likely benign.

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

Publications

14 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 436411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4 link	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 link	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4 link	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4		Q9NQV7
PRDM9	ENST00000502755.6 link	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11	4		ENSP00000425471.2		Q9NQV7D6RD68

Frequencies

GnomAD3 genomes

AF:

0.745

AC:

23756

AN:

31880

Hom.:

8732

Cov.:

show subpopulations

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

African (AFR)

AF:

0.560

AC:

5514

AN:

9846

American (AMR)

AF:

0.698

AC:

9537

AN:

13666

Ashkenazi Jewish (ASJ)

AF:

0.747

AC:

7711

AN:

10328

East Asian (EAS)

AF:

0.593

AC:

15259

AN:

25746

South Asian (SAS)

AF:

0.807

AC:

27793

AN:

34422

European-Finnish (FIN)

AF:

0.871

AC:

31537

AN:

36204

Middle Eastern (MID)

AF:

0.817

AC:

2449

AN:

2998

European-Non Finnish (NFE)

AF:

0.780

AC:

169285

AN:

216948

Other (OTH)

AF:

0.733

AC:

15216

AN:

20760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.547

Heterozygous variant carriers

2301

4603

6904

9206

11507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

640

1280

1920

2560

3200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

African (AFR)

AF:

0.540

AC:

4091

AN:

7570

American (AMR)

AF:

0.773

AC:

2479

AN:

3206

Ashkenazi Jewish (ASJ)

AF:

0.811

AC:

738

AN:

910

East Asian (EAS)

AF:

0.645

AC:

591

AN:

916

South Asian (SAS)

AF:

0.773

AC:

379

AN:

490

European-Finnish (FIN)

AF:

0.823

AC:

1638

AN:

1990

Middle Eastern (MID)

AF:

0.857

AC:

AN:

European-Non Finnish (NFE)

AF:

0.825

AC:

13416

AN:

16264

Other (OTH)

AF:

0.758

AC:

323

AN:

426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.589

Heterozygous variant carriers

195

390

584

779

974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20044539, 22291443, 20818382) -

not specified

Benign:1

Aug 19, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

-16

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over