5-23522680-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_020227.4(PRDM9):c.677A>T(p.Lys226Met) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.132

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-23522680-A-T is Pathogenic according to our data. Variant chr5-23522680-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1120013.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19972903).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.677A>T	p.Lys226Met	missense_variant	8/11	ENST00000296682.4
PRDM9	NM_001376900.1	c.677A>T	p.Lys226Met	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.677A>T	p.Lys226Met	missense_variant	8/11	1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.677A>T	p.Lys226Met	missense_variant	8/11	4
PRDM9	ENST00000635252.1	c.500A>T	p.Lys167Met	missense_variant	8/11	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Genetic non-acquired premature ovarian failure Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

May 14, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.044
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	.;D
Vest4		0.47
MutPred		0.34		.;Loss of methylation at K226 (P = 0.0071);
MVP		0.58
MPC		0.64
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.62
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-23522789;