5-23527279-A-G

Position:

• chr5-23527279-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):​c.2191A>G​(p.Asn731Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.09

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010199219).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.2191A>G	p.Asn731Asp	missense_variant	11/11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.2191A>G	p.Asn731Asp	missense_variant	11/11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.2191A>G	p.Asn731Asp	missense_variant	11/11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.2191A>G	p.Asn731Asp	missense_variant	11/11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 120 AN: 42314 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00617

Gnomad AMI AF: 0.0106

Gnomad AMR AF: 0.00254

Gnomad ASJ AF: 0.00266

Gnomad EAS AF: 0.00440

Gnomad SAS AF: 0.00340

Gnomad FIN AF: 0.000353

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.00168

GnomAD3 exomes AF: 0.0000323 AC: 6 AN: 185920 Hom.: 0 AF XY: 0.00000965 AC XY: 1 AN XY: 103634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000836

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000405 AC: 48 AN: 1185980 Hom.: 0 Cov.: 35 AF XY: 0.0000425 AC XY: 25 AN XY: 588262

Gnomad4 AFR exome AF: 0.000247

Gnomad4 AMR exome AF: 0.0000648

Gnomad4 ASJ exome AF: 0.0000574

Gnomad4 EAS exome AF: 0.000218

Gnomad4 SAS exome AF: 0.000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000235

Gnomad4 OTH exome AF: 0.0000456

GnomAD4 genome AF: 0.00288 AC: 122 AN: 42342 Hom.: 0 Cov.: 0 AF XY: 0.00275 AC XY: 58 AN XY: 21102

Gnomad4 AFR AF: 0.00638

Gnomad4 AMR AF: 0.00253

Gnomad4 ASJ AF: 0.00266

Gnomad4 EAS AF: 0.00441

Gnomad4 SAS AF: 0.00338

Gnomad4 FIN AF: 0.000353

Gnomad4 NFE AF: 0.00170

Gnomad4 OTH AF: 0.00166

Alfa AF: 0.000713 Hom.: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.52
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.017	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.45	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.024
Sift	Benign	0.45	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.029
MVP		0.15
MPC		0.14
ClinPred		0.033	T
GERP RS		-2.1
Varity_R		0.10
gMVP		0.023

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: rs58979818; hg19: chr5-23527388; COSMIC: COSV57003338; COSMIC: COSV57003338;