chr5-23510000-G-T

Position:

• chr5-23510000-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020227.4(PRDM9):​c.274G>T​(p.Asp92Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27280426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.274G>T	p.Asp92Tyr	missense_variant	4/11	ENST00000296682.4
PRDM9	NM_001376900.1	c.274G>T	p.Asp92Tyr	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.274G>T	p.Asp92Tyr	missense_variant	4/11	1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.274G>T	p.Asp92Tyr	missense_variant	4/11	4
PRDM9	ENST00000635252.1	c.97G>T	p.Asp33Tyr	missense_variant	4/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.274G>T (p.D92Y) alteration is located in exon 4 (coding exon 3) of the PRDM9 gene. This alteration results from a G to T substitution at nucleotide position 274, causing the aspartic acid (D) at amino acid position 92 to be replaced by a tyrosine (Y). 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	0.25
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	.;.;M
MutationTaster	Benign	0.82	N
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	.;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.44
MutPred		0.27		.;Gain of phosphorylation at D92 (P = 0.0023);Gain of phosphorylation at D92 (P = 0.0023);
MVP		0.35
MPC		0.48
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.36
gMVP		0.036

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: chr5-23510109; COSMIC: COSV57010895;