chr5-23527456-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020227.4(PRDM9):c.2368A>C(p.Asn790His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,436,540 control chromosomes in the GnomAD database, including 454 homozygotes. 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 (★★).

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 18)

Exomes 𝑓: 0.022 ( 429 hom. )

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.52

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027828813).

BP6

Variant 5-23527456-A-C is Benign according to our data. Variant chr5-23527456-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 436412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.017 (1711/100384) while in subpopulation AMR AF = 0.0239 (200/8380). AF 95% confidence interval is 0.0212. There are 25 homozygotes in GnomAd4. There are 845 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4 link	c.2368A>C	p.Asn790His	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 link	c.2368A>C	p.Asn790His	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.2368A>C	p.Asn790His	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4		Q9NQV7
PRDM9	ENST00000502755.6 link	c.2368A>C	p.Asn790His	missense_variant	Exon 11 of 11	4		ENSP00000425471.2		Q9NQV7D6RD68

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

1713

AN:

100376

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00856

Gnomad AMI

AF:

0.0149

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0249

Gnomad EAS

AF:

0.000607

Gnomad SAS

AF:

0.00380

Gnomad FIN

AF:

0.0235

Gnomad MID

AF:

0.0323

Gnomad NFE

AF:

0.0199

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0232

AC:

4974

AN:

213972

AF XY:

0.0229

show subpopulations

Gnomad AFR exome

AF:

0.0183

Gnomad AMR exome

AF:

0.0197

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.00249

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0260

GnomAD4 exome

AF:

0.0221

AC:

29502

AN:

1336156

Hom.:

429

Cov.:

AF XY:

0.0220

AC XY:

14663

AN XY:

665838

show subpopulations

African (AFR)

AF:

0.0219

AC:

435

AN:

19890

American (AMR)

AF:

0.0249

AC:

958

AN:

38434

Ashkenazi Jewish (ASJ)

AF:

0.0409

AC:

965

AN:

23598

East Asian (EAS)

AF:

0.00299

AC:

108

AN:

36136

South Asian (SAS)

AF:

0.00810

AC:

638

AN:

78728

European-Finnish (FIN)

AF:

0.0245

AC:

1216

AN:

49734

Middle Eastern (MID)

AF:

0.0368

AC:

181

AN:

4920

European-Non Finnish (NFE)

AF:

0.0230

AC:

23698

AN:

1031308

Other (OTH)

AF:

0.0244

AC:

1303

AN:

53408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

1877

3754

5631

7508

9385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.0170

AC:

1711

AN:

100384

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

845

AN XY:

47242

show subpopulations

African (AFR)

AF:

0.00856

AC:

188

AN:

21972

American (AMR)

AF:

0.0239

AC:

200

AN:

8380

Ashkenazi Jewish (ASJ)

AF:

0.0249

AC:

AN:

2886

East Asian (EAS)

AF:

0.000608

AC:

AN:

3292

South Asian (SAS)

AF:

0.00381

AC:

AN:

2888

European-Finnish (FIN)

AF:

0.0235

AC:

113

AN:

4818

Middle Eastern (MID)

AF:

0.0328

AC:

AN:

122

European-Non Finnish (NFE)

AF:

0.0199

AC:

1075

AN:

54036

Other (OTH)

AF:

0.0267

AC:

AN:

1384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00540

Hom.:

TwinsUK

AF:

0.0477

AC:

177

ALSPAC

AF:

0.0506

AC:

195

ExAC

AF:

0.0234

AC:

2831

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.063

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.098

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.027

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-2.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.0

REVEL

Benign

0.027

Sift

Benign

0.12

Sift4G

Benign

0.81

Polyphen

0.050

Vest4

0.099

MPC

0.13

ClinPred

0.0058

GERP RS

-6.2

Varity_R

0.14

gMVP

0.030

Mutation Taster

=96/4

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