Genetic Variant NM_020227.4:c.1706T>C (chr5-23526794-T-C) – 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.1706T>C(p.Ile569Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I569N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00092 ( 1 hom., cov: 29)

Exomes 𝑓: 0.000048 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -9.39

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01857686).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	NM_020227.4	MANE Select	c.1706T>C	p.Ile569Thr	missense	Exon 11 of 11	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.1706T>C	p.Ile569Thr	missense	Exon 11 of 11	NP_001363829.1	Q9NQV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.1706T>C	p.Ile569Thr	missense	Exon 11 of 11	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.1706T>C	p.Ile569Thr	missense	Exon 11 of 11	ENSP00000425471.2	Q9NQV7

Frequencies

GnomAD3 genomes

AF:

0.000913

AC:

AN:

97482

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000773

Gnomad ASJ

AF:

0.000413

Gnomad EAS

AF:

0.00110

Gnomad SAS

AF:

0.000374

Gnomad FIN

AF:

0.00112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000504

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.0000645

AC:

AN:

201690

AF XY:

0.0000450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000793

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000105

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000484

AC:

AN:

1177874

Hom.:

Cov.:

AF XY:

0.0000566

AC XY:

AN XY:

583426

show subpopulations

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

African (AFR)

AF:

0.000525

AC:

AN:

22864

American (AMR)

AF:

0.0000702

AC:

AN:

28498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16184

East Asian (EAS)

AF:

0.00

AC:

AN:

12762

South Asian (SAS)

AF:

0.000201

AC:

AN:

74588

European-Finnish (FIN)

AF:

0.0000287

AC:

AN:

34834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4404

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

941288

Other (OTH)

AF:

0.000118

AC:

AN:

42452

⚠️ 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: 0.379

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000923

AC:

AN:

97548

Hom.:

Cov.:

AF XY:

0.000783

AC XY:

AN XY:

48544

show subpopulations

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

African (AFR)

AF:

0.00177

AC:

AN:

25424

American (AMR)

AF:

0.000772

AC:

AN:

10356

Ashkenazi Jewish (ASJ)

AF:

0.000413

AC:

AN:

2424

East Asian (EAS)

AF:

0.00110

AC:

AN:

2728

South Asian (SAS)

AF:

0.000373

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

6262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

118

European-Non Finnish (NFE)

AF:

0.000504

AC:

AN:

45664

Other (OTH)

AF:

0.00141

AC:

AN:

1414

⚠️ 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: 0.265

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:

0.00115

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0050

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.025

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.11

M_CAP

Benign

0.00054

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.25

PhyloP100

-9.4

PrimateAI

Benign

0.41

PROVEAN

Benign

0.43

REVEL

Benign

0.0080

Sift

Benign

0.65

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.013

MVP

0.11

MPC

0.16

ClinPred

0.044

GERP RS

-4.6

Varity_R

0.032

gMVP

0.013

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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