Genetic Variant PRDM9:p.Asn731Asp (chr5-23527279-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):c.2191A>G(p.Asn731Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000040 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.09

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010199219).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	NM_020227.4	MANE Select	c.2191A>G	p.Asn731Asp	missense	Exon 11 of 11	NP_064612.2
	PRDM9	NM_001376900.1		c.2191A>G	p.Asn731Asp	missense	Exon 11 of 11	NP_001363829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.2191A>G	p.Asn731Asp	missense	Exon 11 of 11	ENSP00000296682.4
	PRDM9	ENST00000502755.6	TSL:4	c.2191A>G	p.Asn731Asp	missense	Exon 11 of 11	ENSP00000425471.2

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

120

AN:

42314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00617

Gnomad AMI

AF:

0.0106

Gnomad AMR

AF:

0.00254

Gnomad ASJ

AF:

0.00266

Gnomad EAS

AF:

0.00440

Gnomad SAS

AF:

0.00340

Gnomad FIN

AF:

0.000353

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00170

Gnomad OTH

AF:

0.00168

GnomAD2 exomes

AF:

0.0000323

AC:

AN:

185920

AF XY:

0.00000965

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000897

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000227

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000405

AC:

AN:

1185980

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

588262

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000247

AC:

AN:

24310

American (AMR)

AF:

0.0000648

AC:

AN:

30842

Ashkenazi Jewish (ASJ)

AF:

0.0000574

AC:

AN:

17426

East Asian (EAS)

AF:

0.000218

AC:

AN:

18310

South Asian (SAS)

AF:

0.000138

AC:

AN:

72284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36530

Middle Eastern (MID)

AF:

0.000222

AC:

AN:

4508

European-Non Finnish (NFE)

AF:

0.0000235

AC:

AN:

937912

Other (OTH)

AF:

0.0000456

AC:

AN:

43858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

AF:

0.00288

AC:

122

AN:

42342

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

AN XY:

21102

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00638

AC:

AN:

8932

American (AMR)

AF:

0.00253

AC:

AN:

4342

Ashkenazi Jewish (ASJ)

AF:

0.00266

AC:

AN:

1126

East Asian (EAS)

AF:

0.00441

AC:

AN:

1360

South Asian (SAS)

AF:

0.00338

AC:

AN:

1182

European-Finnish (FIN)

AF:

0.000353

AC:

AN:

2832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00170

AC:

AN:

21716

Other (OTH)

AF:

0.00166

AC:

AN:

602

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000713

Hom.:

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.46

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.025

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0037

LIST_S2

Benign

0.017

M_CAP

Benign

0.0012

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.45

PhyloP100

-4.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.14

REVEL

Benign

0.024

Sift

Benign

0.45

Sift4G

Benign

0.57

Polyphen

0.0

Vest4

0.029

MVP

0.15

MPC

0.14

ClinPred

0.033

GERP RS

-2.1

Varity_R

0.10

gMVP

0.023

Mutation Taster

=97/3

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over