NM_020227.4:c.301+39_301+44delTTTTTT

Variant names:

• chr5-23510049-ATTTTTT-A
• rs34033521
• NM_020227.4:c.301+39_301+44delTTTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020227.4(PRDM9):​c.301+39_301+44delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,252,076 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.301+39_301+44delTTTTTT		intron_variant	Intron 4 of 10	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.301+39_301+44delTTTTTT		intron_variant	Intron 4 of 10		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.301+23_301+28delTTTTTT		intron_variant	Intron 4 of 10	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.301+23_301+28delTTTTTT		intron_variant	Intron 4 of 10	4		ENSP00000425471.2
PRDM9	ENST00000635252.1	c.124+23_124+28delTTTTTT		intron_variant	Intron 4 of 10	5		ENSP00000489227.1

Frequencies

GnomAD3 genomes AF: 0.0000189 AC: 2 AN: 105722 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000701

GnomAD3 exomes AF: 0.0000519 AC: 5 AN: 96360 Hom.: 0 AF XY: 0.0000392 AC XY: 2 AN XY: 51080

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.000134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000508

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 145 AN: 1146354 Hom.: 0 AF XY: 0.000129 AC XY: 74 AN XY: 572960

Gnomad4 AFR exome AF: 0.000398

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.000198

Gnomad4 EAS exome AF: 0.000189

Gnomad4 SAS exome AF: 0.0000717

Gnomad4 FIN exome AF: 0.000149

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.0000189 AC: 2 AN: 105722 Hom.: 0 Cov.: 0 AF XY: 0.0000203 AC XY: 1 AN XY: 49318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000701

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;