5-23527530-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_020227.4(PRDM9):c.2442C>A(p.Ser814Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000433 in 1,536,846 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 16)

Exomes 𝑓: 0.00046 ( 44 hom. )

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -7.26

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

new If you want to explore the variant's impact on the transcript NM_020227.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007636249).

BP6

Variant 5-23527530-C-A is Benign according to our data. Variant chr5-23527530-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3388168.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 44 AR gene

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.2442C>A	p.Ser814Arg	missense	Exon 11 of 11	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.2442C>A	p.Ser814Arg	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.2442C>A	p.Ser814Arg	missense	Exon 11 of 11	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.2442C>A	p.Ser814Arg	missense	Exon 11 of 11	ENSP00000425471.2	Q9NQV7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

108700

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000341

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000734

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000382

AC:

AN:

235662

AF XY:

0.0000466

show subpopulations

Gnomad AFR exome

AF:

0.000231

Gnomad AMR exome

AF:

0.0000333

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000461

AC:

659

AN:

1428084

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

310

AN XY:

710478

show subpopulations

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

African (AFR)

AF:

0.00674

AC:

191

AN:

28356

American (AMR)

AF:

0.00106

AC:

AN:

42550

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

24700

East Asian (EAS)

AF:

0.00193

AC:

AN:

37766

South Asian (SAS)

AF:

0.000298

AC:

AN:

83790

European-Finnish (FIN)

AF:

0.0000379

AC:

AN:

52702

Middle Eastern (MID)

AF:

0.00167

AC:

AN:

5404

European-Non Finnish (NFE)

AF:

0.000196

AC:

215

AN:

1095202

Other (OTH)

AF:

0.00120

AC:

AN:

57614

⚠️ 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

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000552

AC:

AN:

108762

Hom.:

Cov.:

AF XY:

0.0000566

AC XY:

AN XY:

53018

show subpopulations

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

African (AFR)

AF:

0.0000409

AC:

AN:

24446

American (AMR)

AF:

0.00

AC:

AN:

11174

Ashkenazi Jewish (ASJ)

AF:

0.000341

AC:

AN:

2932

East Asian (EAS)

AF:

0.00

AC:

AN:

3402

South Asian (SAS)

AF:

0.00

AC:

AN:

2920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

154

European-Non Finnish (NFE)

AF:

0.0000734

AC:

AN:

54532

Other (OTH)

AF:

0.00

AC:

AN:

1514

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000759021), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

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:

0.000422

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.017

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.041

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.036

M_CAP

Benign

0.0026

MetaRNN

Benign

0.0076

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.91

PhyloP100

-7.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.4

REVEL

Benign

0.028

Sift

Benign

0.29

Sift4G

Benign

0.27

Varity_R

0.16

gMVP

0.020

Mutation Taster

=92/8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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