chr5-23510049-ATTTT-A

Variant names:

• chr5-23510049-ATTTT-A
• rs34033521
• NM_020227.4:c.301+41_301+44delTTTT

Variant summary

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

The NM_020227.4(PRDM9):​c.301+41_301+44delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,244,506 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 0.000028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0036 (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+41_301+44delTTTT		intron_variant	Intron 4 of 10	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.301+41_301+44delTTTT		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+26delTTTT		intron_variant	Intron 4 of 10	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.301+23_301+26delTTTT		intron_variant	Intron 4 of 10	4		ENSP00000425471.2
PRDM9	ENST00000635252.1	c.124+23_124+26delTTTT		intron_variant	Intron 4 of 10	5		ENSP00000489227.1

Frequencies

GnomAD3 genomes AF: 0.0000284 AC: 3 AN: 105714 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000182

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00364 AC: 4142 AN: 1138792 Hom.: 0 AF XY: 0.00353 AC XY: 2010 AN XY: 569272

Gnomad4 AFR exome AF: 0.00740

Gnomad4 AMR exome AF: 0.00574

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.00646

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.0000284 AC: 3 AN: 105714 Hom.: 0 Cov.: 0 AF XY: 0.0000203 AC XY: 1 AN XY: 49314

Gnomad4 AFR AF: 0.0000395

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000231

Gnomad4 NFE AF: 0.0000182

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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;