Variant 5-23522641-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_020227.4(PRDM9):c.638T>G(p.Ile213Ser) 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PRDM9
NM_020227.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.656

Variant links:

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]

PRDM9 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-23522641-T-G is Pathogenic according to our data. Variant chr5-23522641-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1120012.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.19711438). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4 linkuse as main transcript	c.638T>G	p.Ile213Ser	missense_variant	8/11	ENST00000296682.4
PRDM9	NM_001376900.1 linkuse as main transcript	c.638T>G	p.Ile213Ser	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PRDM9	ENST00000296682.4 linkuse as main transcript	c.638T>G	p.Ile213Ser	missense_variant	8/11	1	NM_020227.4	P1
PRDM9	ENST00000502755.6 linkuse as main transcript	c.638T>G	p.Ile213Ser	missense_variant	8/11	4
PRDM9	ENST00000635252.1 linkuse as main transcript	c.461T>G	p.Ile154Ser	missense_variant	8/11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

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

Uncertain

0.42

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.8

.;M

MutationTaster

Benign

0.58

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.8

.;N

REVEL

Benign

0.062

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.025

D;T

Polyphen

0.51

.;P

Vest4

0.53

MutPred

0.57

.;Gain of disorder (P = 0.0071);

MVP

0.58

MPC

0.28

ClinPred

0.95

GERP RS

3.1

Varity_R

0.62

gMVP

0.093

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over