dbSNP rs772744700: PRDM9:p.Ile569Asn (chr5-23526794-T-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_020227.4(PRDM9):c.1706T>A(p.Ile569Asn) 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000070 ( 0 hom., cov: 29)

Exomes 𝑓: 8.4e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03966716).

BP6

Variant 5-23526794-T-A is Benign according to our data. Variant chr5-23526794-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 436410.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4 link	c.1706T>A	p.Ile569Asn	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 link	c.1706T>A	p.Ile569Asn	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.1706T>A	p.Ile569Asn	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4		Q9NQV7
PRDM9	ENST00000502755.6 link	c.1706T>A	p.Ile569Asn	missense_variant	Exon 11 of 11	4		ENSP00000425471.2		Q9NQV7D6RD68

Frequencies

GnomAD3 genomes

AF:

0.0000704

AC:

AN:

99384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000357

Gnomad SAS

AF:

0.000366

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000216

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

8.45e-7

AC:

AN:

1183724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

586334

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23396

American (AMR)

AF:

0.00

AC:

AN:

29760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16330

East Asian (EAS)

AF:

0.00

AC:

AN:

13574

South Asian (SAS)

AF:

0.00

AC:

AN:

75130

European-Finnish (FIN)

AF:

0.0000286

AC:

AN:

34906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4424

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

943408

Other (OTH)

AF:

0.00

AC:

AN:

42796

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000704

AC:

AN:

99446

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

49390

show subpopulations

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

African (AFR)

AF:

0.000115

AC:

AN:

26038

American (AMR)

AF:

0.0000949

AC:

AN:

10542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2462

East Asian (EAS)

AF:

0.000357

AC:

AN:

2802

South Asian (SAS)

AF:

0.000366

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

128

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

46298

Other (OTH)

AF:

0.00

AC:

AN:

1438

⚠️ 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: 0.254

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 16, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.13

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.056

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.00036

LIST_S2

Benign

0.35

M_CAP

Benign

0.00064

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.24

PhyloP100

-9.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.48

REVEL

Benign

0.011

Sift

Benign

0.50

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.11

MutPred

0.33

Loss of stability (P = 0.0502);

MVP

0.17

MPC

0.26

ClinPred

0.042

GERP RS

-4.6

Varity_R

0.046

gMVP

0.024

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over