Genetic Variant NM_020227.4:c.1706T>G (chr5-23526794-T-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.1706T>G(p.Ile569Ser) 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 0.00022 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000049 ( 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=0.020576656).

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.1706T>G	p.Ile569Ser	missense	Exon 11 of 11	NP_064612.2
	PRDM9	NM_001376900.1		c.1706T>G	p.Ile569Ser	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.1706T>G	p.Ile569Ser	missense	Exon 11 of 11	ENSP00000296682.4
	PRDM9	ENST00000502755.6	TSL:4	c.1706T>G	p.Ile569Ser	missense	Exon 11 of 11	ENSP00000425471.2

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

98416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000777

Gnomad AMI

AF:

0.00206

Gnomad AMR

AF:

0.0000957

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000728

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.000619

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000174

Gnomad OTH

AF:

0.000709

GnomAD2 exomes

AF:

0.00000496

AC:

AN:

201690

AF XY:

0.00000899

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000493

AC:

AN:

1176296

Hom.:

Cov.:

AF XY:

0.0000446

AC XY:

AN XY:

582620

show subpopulations

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

African (AFR)

AF:

0.0000862

AC:

AN:

23198

American (AMR)

AF:

0.0000343

AC:

AN:

29192

Ashkenazi Jewish (ASJ)

AF:

0.000186

AC:

AN:

16100

East Asian (EAS)

AF:

0.000916

AC:

AN:

13102

South Asian (SAS)

AF:

0.00

AC:

AN:

74694

European-Finnish (FIN)

AF:

0.0000872

AC:

AN:

34414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4384

European-Non Finnish (NFE)

AF:

0.0000362

AC:

AN:

938906

Other (OTH)

AF:

0.0000709

AC:

AN:

42306

⚠️ 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: 0.297

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:

0.000223

AC:

AN:

98482

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

AN XY:

48940

show subpopulations

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

African (AFR)

AF:

0.0000775

AC:

AN:

25808

American (AMR)

AF:

0.0000957

AC:

AN:

10450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2454

East Asian (EAS)

AF:

0.000728

AC:

AN:

2746

South Asian (SAS)

AF:

0.00112

AC:

AN:

2684

European-Finnish (FIN)

AF:

0.000619

AC:

AN:

6458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

126

European-Non Finnish (NFE)

AF:

0.000174

AC:

AN:

45850

Other (OTH)

AF:

0.000704

AC:

AN:

1420

⚠️ 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: 0.243

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:

0.000602

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.078

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.046

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.00076

LIST_S2

Benign

0.037

M_CAP

Benign

0.00078

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.38

PhyloP100

-9.4

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.24

REVEL

Benign

0.0070

Sift

Benign

0.81

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.030

MutPred

0.37

Gain of disorder (P = 0.0064)

MVP

0.14

MPC

0.18

ClinPred

0.041

GERP RS

-4.6

Varity_R

0.040

gMVP

0.033

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

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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