5-23510049-ATTTTTTTTTTT-ATTTTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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: Variant has high frequency in the AFR (0.00652) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).

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+41_301+44delTTTT		intron	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.301+41_301+44delTTTT		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+26delTTTT		intron	N/A	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.301+23_301+26delTTTT		intron	N/A	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.124+23_124+26delTTTT		intron	N/A	ENSP00000489227.1	A0A0U1RQY2

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

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

African (AFR) AF: 0.00740 AC: 184 AN: 24876

American (AMR) AF: 0.00574 AC: 169 AN: 29462

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 73 AN: 20068

East Asian (EAS) AF: 0.00646 AC: 203 AN: 31442

South Asian (SAS) AF: 0.00213 AC: 148 AN: 69416

European-Finnish (FIN) AF: 0.00386 AC: 155 AN: 40126

Middle Eastern (MID) AF: 0.00600 AC: 25 AN: 4170

European-Non Finnish (NFE) AF: 0.00343 AC: 2989 AN: 872266

Other (OTH) AF: 0.00417 AC: 196 AN: 46966

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

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

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

American (AMR) AF: 0.00 AC: 0 AN: 9342

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: 0.000231 AC: 1 AN: 4328

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

European-Non Finnish (NFE) AF: 0.0000182 AC: 1 AN: 54812

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0763859), which strongly suggests a high chance of mosaicism in these individuals.

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
Mutation Taster		=100/0	polymorphism

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: rs34033521; hg19: chr5-23510158;