5-23510049-A-ATT

Variant names:

• chr5-23510049-A-ATT
• rs34033521
• NM_020227.4:c.301+43_301+44dupTT

Variant summary

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

The NM_020227.4(PRDM9):​c.301+43_301+44dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0062 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• 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 0 ACMG points.

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+43_301+44dupTT		intron	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.301+43_301+44dupTT		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+22_301+23insTT		intron	N/A	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.301+22_301+23insTT		intron	N/A	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.124+22_124+23insTT		intron	N/A	ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 327 AN: 105692 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00277

Gnomad MID AF: 0.00917

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00421

GnomAD2 exomes AF: 0.00638 AC: 615 AN: 96360 AF XY: 0.00644

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00197

Gnomad FIN exome AF: 0.00820

Gnomad NFE exome AF: 0.00630

Gnomad OTH exome AF: 0.00385

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00622 AC: 7087 AN: 1139582 Hom.: 5 Cov.: 0 AF XY: 0.00625 AC XY: 3562 AN XY: 569616

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

African (AFR) AF: 0.00564 AC: 141 AN: 24984

American (AMR) AF: 0.00609 AC: 180 AN: 29544

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 274 AN: 19980

East Asian (EAS) AF: 0.00227 AC: 72 AN: 31718

South Asian (SAS) AF: 0.00419 AC: 291 AN: 69448

European-Finnish (FIN) AF: 0.00691 AC: 278 AN: 40232

Middle Eastern (MID) AF: 0.00788 AC: 33 AN: 4188

European-Non Finnish (NFE) AF: 0.00632 AC: 5514 AN: 872458

Other (OTH) AF: 0.00646 AC: 304 AN: 47030

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00309 AC: 327 AN: 105684 Hom.: 0 Cov.: 0 AF XY: 0.00306 AC XY: 151 AN XY: 49312

African (AFR) AF: 0.00726 AC: 184 AN: 25348

American (AMR) AF: 0.00289 AC: 27 AN: 9344

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 10 AN: 2882

East Asian (EAS) AF: 0.00 AC: 0 AN: 3636

South Asian (SAS) AF: 0.00 AC: 0 AN: 2956

European-Finnish (FIN) AF: 0.00277 AC: 12 AN: 4334

Middle Eastern (MID) AF: 0.00990 AC: 2 AN: 202

European-Non Finnish (NFE) AF: 0.00157 AC: 86 AN: 54792

Other (OTH) AF: 0.00418 AC: 6 AN: 1436

Alfa AF: 0.00932 Hom.: 179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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;