rs56001636

Positions:

• chr5-23527299-A-T

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.80

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]

ACMG classification

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/exons	MANE	UniProt
PRDM9	NM_020227.4	c.2211A>T	p.Arg737Ser	missense_variant	11/11	ENST00000296682.4
PRDM9	NM_001376900.1	c.2211A>T	p.Arg737Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.2211A>T	p.Arg737Ser	missense_variant	11/11	1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.2211A>T	p.Arg737Ser	missense_variant	11/11	4

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 70 AN: 64252 Hom.: 0 Cov.: 12

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: 56 AN: 185674 Hom.: 0 AF XY: 0.000310 AC XY: 32 AN XY: 103208

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.: 0 Cov.: 36 AF XY: 0.000101 AC XY: 66 AN XY: 655122

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: 74 AN: 64286 Hom.: 0 Cov.: 12 AF XY: 0.00135 AC XY: 43 AN XY: 31796

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.: 0

ExAC AF: 0.0000167 AC: 2

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	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.15
DANN	Benign	0.37
DEOGEN2	Benign	0.025	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.00075	N
LIST_S2	Benign	0.0069	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.56	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.017	B
Vest4		0.056
MutPred		0.58		Loss of MoRF binding (P = 0.0139);
MVP		0.040
MPC		0.14
ClinPred		0.011	T
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

Other links and lift over

dbSNP: rs56001636; hg19: chr5-23527408;