5-23526794-T-C

Position:

• chr5-23526794-T-C

Variant summary

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

The NM_020227.4(PRDM9):​c.1706T>C​(p.Ile569Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00092 (1 hom., cov: 29)
  • Exomes 𝑓: 0.000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -9.39

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=0.01857686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.1706T>C	p.Ile569Thr	missense_variant	11/11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.1706T>C	p.Ile569Thr	missense_variant	11/11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.1706T>C	p.Ile569Thr	missense_variant	11/11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.1706T>C	p.Ile569Thr	missense_variant	11/11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.000913 AC: 89 AN: 97482 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000773

Gnomad ASJ AF: 0.000413

Gnomad EAS AF: 0.00110

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000504

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000645 AC: 13 AN: 201690 Hom.: 0 AF XY: 0.0000450 AC XY: 5 AN XY: 111182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000793

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000358

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.000230

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000484 AC: 57 AN: 1177874 Hom.: 0 Cov.: 36 AF XY: 0.0000566 AC XY: 33 AN XY: 583426

Gnomad4 AFR exome AF: 0.000525

Gnomad4 AMR exome AF: 0.0000702

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000201

Gnomad4 FIN exome AF: 0.0000287

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000118

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000923 AC: 90 AN: 97548 Hom.: 1 Cov.: 29 AF XY: 0.000783 AC XY: 38 AN XY: 48544

Gnomad4 AFR AF: 0.00177

Gnomad4 AMR AF: 0.000772

Gnomad4 ASJ AF: 0.000413

Gnomad4 EAS AF: 0.00110

Gnomad4 SAS AF: 0.000373

Gnomad4 FIN AF: 0.00112

Gnomad4 NFE AF: 0.000504

Gnomad4 OTH AF: 0.00141

Alfa AF: 0.00115 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0050
DANN	Benign	0.22
DEOGEN2	Benign	0.025	T
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.00054	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.25	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.0080
Sift	Benign	0.65	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.013
MVP		0.11
MPC		0.16
ClinPred		0.044	T
GERP RS		-4.6
Varity_R		0.032
gMVP		0.013

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: rs772744700; hg19: chr5-23526903; COSMIC: COSV57003461; COSMIC: COSV57003461;