5-23527456-A-T

Variant names:

• chr5-23527456-A-T
• rs77287813
• NM_020227.4:c.2368A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020227.4(PRDM9):​c.2368A>T​(p.Asn790Tyr) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N790H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 18)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.52

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13154197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.2368A>T	p.Asn790Tyr	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.2368A>T	p.Asn790Tyr	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	c.2368A>T	p.Asn790Tyr	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.2368A>T	p.Asn790Tyr	missense_variant	Exon 11 of 11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.35
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.10
Sift	Benign	0.064	T
Sift4G	Benign	0.29	T
Polyphen		0.94	P
Vest4		0.10
MutPred		0.56		Gain of phosphorylation at N790 (P = 0.0337);
MVP		0.067
MPC		0.15
ClinPred		0.31	T
GERP RS		-6.2
Varity_R		0.097
gMVP		0.040

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: rs77287813; hg19: chr5-23527565; COSMIC: COSV57010515; COSMIC: COSV57010515;