rs6875787

chr5-23527130-C-Gchr5-23527130-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_020227.4(PRDM9):c.2042C>G(p.Thr681Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. T681T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (8722 hom., cov: 6)
  • Exomes 𝑓: 0.77 (102722 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -15.7

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.4098835E-4).
• BP6: Variant 5-23527130-C-G is Benign according to our data. Variant chr5-23527130-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 436411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.2042C>G	p.Thr681Ser	missense_variant	11/11	ENST00000296682.4
PRDM9	NM_001376900.1	c.2042C>G	p.Thr681Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.2042C>G	p.Thr681Ser	missense_variant	11/11	1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.2042C>G	p.Thr681Ser	missense_variant	11/11	4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 23756 AN: 31880 Hom.: 8732 Cov.: 6 FAILED QC

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.750

Gnomad AMR AF: 0.773

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.823

Gnomad MID AF: 0.857

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.761

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.766 AC: 284301 AN: 370918 Hom.: 102722 Cov.: 0 AF XY: 0.773 AC XY: 154247 AN XY: 199466

Gnomad4 AFR exome AF: 0.560

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.747

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.807

Gnomad4 FIN exome AF: 0.871

Gnomad4 NFE exome AF: 0.780

Gnomad4 OTH exome AF: 0.733

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.745 AC: 23745 AN: 31888 Hom.: 8722 Cov.: 6 AF XY: 0.748 AC XY: 12168 AN XY: 16278

Gnomad4 AFR AF: 0.540

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.823

Gnomad4 NFE AF: 0.825

Gnomad4 OTH AF: 0.758

ExAC AF: 0.213 AC: 5702

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 19, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

This variant is associated with the following publications: (PMID: 20044539, 22291443, 20818382) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0010
Dann	Benign	0.23
DEOGEN2	Benign	0.027	T
Eigen	Benign	-3.0
Eigen_PC	Benign	-3.1
FATHMM_MKL	Benign	0.00079	N
LIST_S2	Benign	0.0080	T
MetaRNN	Benign	0.00064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.0060
Sift	Benign	0.99	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.0030
MutPred		0.38		Loss of phosphorylation at T681 (P = 0.0394);
MPC		0.11
ClinPred		0.043	T
GERP RS		-5.3
Varity_R		0.022
gMVP		0.018

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: rs6875787; hg19: chr5-23527239; COSMIC: COSV57002015; COSMIC: COSV57002015;