5-23521035-G-C

Variant names:

• chr5-23521035-G-C
• rs764939554
• NM_020227.4:c.364G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020227.4(PRDM9):​c.364G>C​(p.Ala122Pro) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A122S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0390
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097767204).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	NM_020227.4	MANE Select	c.364G>C	p.Ala122Pro	missense	Exon 6 of 11	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.364G>C	p.Ala122Pro	missense	Exon 6 of 11	NP_001363829.1	Q9NQV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.364G>C	p.Ala122Pro	missense	Exon 6 of 11	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.364G>C	p.Ala122Pro	missense	Exon 6 of 11	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.187G>C	p.Ala63Pro	missense	Exon 6 of 11	ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.3
DANN	Benign	0.87
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.039
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.053
Sift	Uncertain	0.028	D
Sift4G	Benign	0.27	T
Polyphen		0.95	P
Vest4		0.13
MutPred		0.25		Loss of MoRF binding (P = 0.0388)
MVP		0.27
MPC		0.16
ClinPred		0.17	T
GERP RS		-0.51
Varity_R		0.12
gMVP		0.019
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs764939554; hg19: chr5-23521144;