rs62342744

Variant names:

• chr5-23522263-C-T
• rs62342744
• NM_020227.4:c.509-41C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.540
• 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: Benign. The variant received -20 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 VariationId is 1226826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	NM_020227.4	MANE Select	c.509-41C>T		intron	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.509-41C>T		intron	N/A	NP_001363829.1	Q9NQV7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.509-41C>T		intron	N/A	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.509-41C>T		intron	N/A	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.332-41C>T		intron	N/A	ENSP00000489227.1	A0A0U1RQY2

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

GnomAD2 exomes AF: 0.0567 AC: 14106 AN: 249000 AF XY: 0.0575

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 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

African (AFR) AF: 0.0218 AC: 681 AN: 31190

American (AMR) AF: 0.0569 AC: 2537 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3586 AN: 25534

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39128

South Asian (SAS) AF: 0.0268 AC: 2252 AN: 84040

European-Finnish (FIN) AF: 0.0297 AC: 1583 AN: 53342

Middle Eastern (MID) AF: 0.0851 AC: 474 AN: 5570

European-Non Finnish (NFE) AF: 0.0754 AC: 76660 AN: 1016660

Other (OTH) AF: 0.0672 AC: 3818 AN: 56850

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

African (AFR) AF: 0.0228 AC: 944 AN: 41486

American (AMR) AF: 0.0830 AC: 1267 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0233 AC: 112 AN: 4816

European-Finnish (FIN) AF: 0.0282 AC: 299 AN: 10592

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5126 AN: 68004

Other (OTH) AF: 0.0828 AC: 175 AN: 2114

Alfa AF: 0.0746 Hom.: 99

Bravo AF: 0.0592

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.9
DANN	Benign	0.72
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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: rs62342744; hg19: chr5-23522372;