rs58945509

Variant names:

• chr5-23527372-C-A
• rs58945509
• NM_020227.4:c.2284C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-23527372-C-A
• chr5-23527372-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):​c.2284C>A​(p.His762Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 11)
  • Exomes 𝑓: 0.0000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -20.0
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01620987).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	NM_020227.4	MANE Select	c.2284C>A	p.His762Asn	missense	Exon 11 of 11	NP_064612.2
	PRDM9	NM_001376900.1		c.2284C>A	p.His762Asn	missense	Exon 11 of 11	NP_001363829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.2284C>A	p.His762Asn	missense	Exon 11 of 11	ENSP00000296682.4
	PRDM9	ENST00000502755.6	TSL:4	c.2284C>A	p.His762Asn	missense	Exon 11 of 11	ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.0000142 AC: 1 AN: 70412 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.0000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 229848 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000290 AC: 4 AN: 1381016 Hom.: 0 Cov.: 37 AF XY: 0.00000291 AC XY: 2 AN XY: 686948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26328

American (AMR) AF: 0.00 AC: 0 AN: 38894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23020

East Asian (EAS) AF: 0.00 AC: 0 AN: 34496

South Asian (SAS) AF: 0.00 AC: 0 AN: 81758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5084

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1066900

Other (OTH) AF: 0.00 AC: 0 AN: 54336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000482131), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000142 AC: 1 AN: 70412 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 33894

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000821 AC: 1 AN: 12174

American (AMR) AF: 0.00 AC: 0 AN: 6312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2166

East Asian (EAS) AF: 0.00 AC: 0 AN: 2298

South Asian (SAS) AF: 0.00 AC: 0 AN: 1686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 40736

Other (OTH) AF: 0.00 AC: 0 AN: 948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0010
DANN	Benign	0.32
DEOGEN2	Benign	0.021	T
Eigen	Benign	-3.0
Eigen_PC	Benign	-3.0
FATHMM_MKL	Benign	0.00033	N
LIST_S2	Benign	0.019	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N
PhyloP100		-20
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.071
MVP		0.16
MPC		0.14
ClinPred		0.031	T
GERP RS		-5.9
Varity_R		0.16
gMVP		0.030
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs58945509; hg19: chr5-23527481;