rs55862350

Positions:

• chr5-23527373-A-C
• chr5-23527373-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020227.4(PRDM9):​c.2285A>C​(p.His762Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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: not found (cov: 10)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.2285A>C	p.His762Pro	missense_variant	11/11	ENST00000296682.4
PRDM9	NM_001376900.1	c.2285A>C	p.His762Pro	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.2285A>C	p.His762Pro	missense_variant	11/11	1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.2285A>C	p.His762Pro	missense_variant	11/11	4

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.87
DANN	Benign	0.13
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.013	T
M_CAP	Benign	0.00090	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.056
Sift	Benign	0.12	T
Sift4G	Benign	0.28	T
Polyphen		0.024	B
Vest4		0.13
MutPred		0.53		Loss of helix (P = 0.0626);
MVP		0.055
MPC		0.31
ClinPred		0.099	T
GERP RS		-5.9
Varity_R		0.44
gMVP		0.23

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: rs55862350; hg19: chr5-23527482;