chr5-23527130-C-G

Variant names:

• chr5-23527130-C-G
• rs6875787
• NM_020227.4:c.2042C>G

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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:3
• 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 rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.2042C>G	p.Thr681Ser	missense_variant	Exon 11 of 11	4		ENSP00000425471.2

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not specified Benign:1

Aug 19, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;