dbSNP rs56001636: PRDM9:p.Arg737Ser (chr5-23527299-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):c.2211A>T(p.Arg737Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 12)

Exomes 𝑓: 0.00010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -7.80

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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019393176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4 link	c.2211A>T	p.Arg737Ser	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 link	c.2211A>T	p.Arg737Ser	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.2211A>T	p.Arg737Ser	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4		Q9NQV7
PRDM9	ENST00000502755.6 link	c.2211A>T	p.Arg737Ser	missense_variant	Exon 11 of 11	4		ENSP00000425471.2		Q9NQV7D6RD68

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

AN:

64252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00242

Gnomad AMI

AF:

0.00294

Gnomad AMR

AF:

0.000639

Gnomad ASJ

AF:

0.00111

Gnomad EAS

AF:

0.00133

Gnomad SAS

AF:

0.00116

Gnomad FIN

AF:

0.000692

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000731

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000302

AC:

AN:

185674

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

103208

show subpopulations

Gnomad AFR exome

AF:

0.000208

Gnomad AMR exome

AF:

0.000278

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000282

Gnomad SAS exome

AF:

0.0000848

Gnomad FIN exome

AF:

0.000259

Gnomad NFE exome

AF:

0.000415

Gnomad OTH exome

AF:

0.000258

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000101

AC:

133

AN:

1318176

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

655122

show subpopulations

Gnomad4 AFR exome

AF:

0.000225

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000193

Gnomad4 SAS exome

AF:

0.0000509

Gnomad4 FIN exome

AF:

0.000622

Gnomad4 NFE exome

AF:

0.0000772

Gnomad4 OTH exome

AF:

0.0000971

GnomAD4 genome

AF:

0.00115

AC:

AN:

64286

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

AN XY:

31796

show subpopulations

Gnomad4 AFR

AF:

0.00266

Gnomad4 AMR

AF:

0.000798

Gnomad4 ASJ

AF:

0.00111

Gnomad4 EAS

AF:

0.00133

Gnomad4 SAS

AF:

0.00116

Gnomad4 FIN

AF:

0.000692

Gnomad4 NFE

AF:

0.000731

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0513

Hom.:

ExAC

AF:

0.0000167

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.15

DANN

Benign

0.37

DEOGEN2

Benign

0.025

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.00075

LIST_S2

Benign

0.0069

M_CAP

Benign

0.0011

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.56

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.46

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

0.78

Polyphen

0.017

Vest4

0.056

MutPred

0.58

Loss of MoRF binding (P = 0.0139);

MVP

0.040

MPC

0.14

ClinPred

0.011

GERP RS

-3.8

Varity_R

0.32

gMVP

0.056

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over