5-23510049-ATTTTTTTTTTT-ATTTT

Variant names:

• chr5-23510049-ATTTTTTT-A
• rs34033521
• NM_020227.4:c.301+38_301+44delTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020227.4(PRDM9):​c.301+38_301+44delTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,252,472 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 0.0000095 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.301+38_301+44delTTTTTTT		intron	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.301+38_301+44delTTTTTTT		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.301+23_301+29delTTTTTTT		intron	N/A	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.301+23_301+29delTTTTTTT		intron	N/A	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.124+23_124+29delTTTTTTT		intron	N/A	ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes AF: 0.00000946 AC: 1 AN: 105722 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000340 AC: 39 AN: 1146750 Hom.: 0 AF XY: 0.0000419 AC XY: 24 AN XY: 573176

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000398 AC: 1 AN: 25122

American (AMR) AF: 0.00 AC: 0 AN: 29720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20196

East Asian (EAS) AF: 0.0000628 AC: 2 AN: 31826

South Asian (SAS) AF: 0.0000430 AC: 3 AN: 69762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4204

European-Non Finnish (NFE) AF: 0.0000353 AC: 31 AN: 878222

Other (OTH) AF: 0.0000423 AC: 2 AN: 47306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000346823), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000946 AC: 1 AN: 105722 Hom.: 0 Cov.: 0 AF XY: 0.0000203 AC XY: 1 AN XY: 49318

African (AFR) AF: 0.0000395 AC: 1 AN: 25324

American (AMR) AF: 0.00 AC: 0 AN: 9344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2882

East Asian (EAS) AF: 0.00 AC: 0 AN: 3650

South Asian (SAS) AF: 0.00 AC: 0 AN: 2978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54812

Other (OTH) AF: 0.00 AC: 0 AN: 1426

Alfa AF: 0.00 Hom.: 179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34033521; hg19: chr5-23510158;