5-23522263-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020227.4(PRDM9):c.509-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,509,014 control chromosomes in the GnomAD database, including 3,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (353 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3579 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.540

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-23522263-C-T is Benign according to our data. Variant chr5-23522263-C-T is described in ClinVar as [Benign]. Clinvar id is 1226826.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.509-41C>T		intron_variant		ENST00000296682.4
PRDM9	NM_001376900.1	c.509-41C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.509-41C>T		intron_variant		1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.509-41C>T		intron_variant		4
PRDM9	ENST00000635252.1	c.332-41C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8507 AN: 152010 Hom.: 353 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0832

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0841

GnomAD3 exomes AF: 0.0567 AC: 14106 AN: 249000 Hom.: 566 AF XY: 0.0575 AC XY: 7769 AN XY: 135084

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0271

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0700

GnomAD4 exome AF: 0.0675 AC: 91592 AN: 1356886 Hom.: 3579 Cov.: 25 AF XY: 0.0669 AC XY: 45596 AN XY: 681360

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.0569

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0268

Gnomad4 FIN exome AF: 0.0297

Gnomad4 NFE exome AF: 0.0754

Gnomad4 OTH exome AF: 0.0672

GnomAD4 genome AF: 0.0559 AC: 8499 AN: 152128 Hom.: 353 Cov.: 32 AF XY: 0.0534 AC XY: 3974 AN XY: 74364

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.0830

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0233

Gnomad4 FIN AF: 0.0282

Gnomad4 NFE AF: 0.0754

Gnomad4 OTH AF: 0.0828

Alfa AF: 0.0746 Hom.: 99

Bravo AF: 0.0592

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	7.9
Dann	Benign	0.72

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: rs62342744; hg19: chr5-23522372; COSMIC: COSV104393095;