5-23523239-C-T

Position:

• chr5-23523239-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020227.4(PRDM9):​c.883-52C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 1,565,218 control chromosomes in the GnomAD database, including 655,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54680 hom., cov: 32)
  • Exomes 𝑓: 0.92 (600745 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.121

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-23523239-C-T is Benign according to our data. Variant chr5-23523239-C-T is described in ClinVar as [Benign]. Clinvar id is 1278507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.883-52C>T		intron_variant		ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.883-52C>T		intron_variant			NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.883-52C>T		intron_variant		1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.883-52C>T		intron_variant		4		ENSP00000425471.2
PRDM9	ENST00000635252.1	c.706-52C>T		intron_variant		5		ENSP00000489227.1

Frequencies

GnomAD3 genomes AF: 0.836 AC: 127098 AN: 152002 Hom.: 54680 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.869

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.901

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.934

Gnomad OTH AF: 0.860

GnomAD4 exome AF: 0.920 AC: 1299926 AN: 1413098 Hom.: 600745 Cov.: 31 AF XY: 0.921 AC XY: 649578 AN XY: 705558

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.911

Gnomad4 ASJ exome AF: 0.924

Gnomad4 EAS exome AF: 0.740

Gnomad4 SAS exome AF: 0.910

Gnomad4 FIN exome AF: 0.969

Gnomad4 NFE exome AF: 0.936

Gnomad4 OTH exome AF: 0.896

GnomAD4 genome AF: 0.836 AC: 127135 AN: 152120 Hom.: 54680 Cov.: 32 AF XY: 0.839 AC XY: 62380 AN XY: 74386

Gnomad4 AFR AF: 0.616

Gnomad4 AMR AF: 0.881

Gnomad4 ASJ AF: 0.918

Gnomad4 EAS AF: 0.753

Gnomad4 SAS AF: 0.900

Gnomad4 FIN AF: 0.974

Gnomad4 NFE AF: 0.934

Gnomad4 OTH AF: 0.858

Alfa AF: 0.921 Hom.: 71650

Bravo AF: 0.819

Asia WGS AF: 0.788 AC: 2742 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.6
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1874165; hg19: chr5-23523348; COSMIC: COSV57005608;