NM_020227.4:c.566A>T

Variant names:

• chr5-23522361-A-T
• rs1739343488
• NM_020227.4:c.566A>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.566A>T​(p.His189Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.577

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=0.037715524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.566A>T	p.His189Leu	missense_variant	Exon 7 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.566A>T	p.His189Leu	missense_variant	Exon 7 of 11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.566A>T	p.His189Leu	missense_variant	Exon 7 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.566A>T	p.His189Leu	missense_variant	Exon 7 of 11	4		ENSP00000425471.2
PRDM9	ENST00000635252.1	c.389A>T	p.His130Leu	missense_variant	Exon 7 of 11	5		ENSP00000489227.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566A>T (p.H189L) alteration is located in exon 7 (coding exon 6) of the PRDM9 gene. This alteration results from a A to T substitution at nucleotide position 566, causing the histidine (H) at amino acid position 189 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.055
DANN	Benign	0.31
DEOGEN2	Benign	0.094	.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.24	T;T
M_CAP	Benign	0.00084	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.014
Sift	Benign	1.0	.;T
Sift4G	Benign	0.84	T;T
Polyphen		0.0	.;B
Vest4		0.17
MutPred		0.51		.;Gain of stability (P = 0.0432);
MVP		0.076
MPC		0.15
ClinPred		0.026	T
GERP RS		-7.3
Varity_R		0.072
gMVP		0.023

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: rs1739343488; hg19: chr5-23522470;