5-23510049-ATT-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_020227.4(PRDM9):c.301+43_301+44del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,199,738 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (25 hom., cov: 0)
  • Exomes 𝑓: 0.13 (12 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 5-23510049-ATT-A is Benign according to our data. Variant chr5-23510049-ATT-A is described in ClinVar as [Benign]. Clinvar id is 1295150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.301+43_301+44del		intron_variant		ENST00000296682.4
PRDM9	NM_001376900.1	c.301+43_301+44del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.301+43_301+44del		intron_variant		1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.301+43_301+44del		intron_variant		4
PRDM9	ENST00000635252.1	c.124+43_124+44del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 2743 AN: 105696 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.00839

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.0324

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0338

GnomAD3 exomes AF: 0.138 AC: 13301 AN: 96360 Hom.: 1 AF XY: 0.133 AC XY: 6796 AN XY: 51080

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.0631

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.129 AC: 141083 AN: 1094050 Hom.: 12 AF XY: 0.128 AC XY: 69873 AN XY: 544950

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.0260 AC: 2743 AN: 105688 Hom.: 25 Cov.: 0 AF XY: 0.0251 AC XY: 1240 AN XY: 49314

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.0360

Gnomad4 SAS AF: 0.00846

Gnomad4 FIN AF: 0.00623

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0335

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

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: rs34033521; hg19: chr5-23510158;