chr5-23510049-ATTT-A

Variant names:

• chr5-23510049-ATTT-A
• rs34033521
• NM_020227.4:c.301+42_301+44delTTT

Variant summary

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

The NM_020227.4(PRDM9):​c.301+42_301+44delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,229,448 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.021 (1 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 (0.0337) population. However there is too low homozygotes in high coverage region: (expected more than 108, got 1).

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+42_301+44delTTT		intron	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.301+42_301+44delTTT		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+25delTTT		intron	N/A	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.301+23_301+25delTTT		intron	N/A	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.124+23_124+25delTTT		intron	N/A	ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes AF: 0.000199 AC: 21 AN: 105710 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000395

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: 0.000924

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000912

Gnomad OTH AF: 0.000702

GnomAD2 exomes AF: 0.0215 AC: 2072 AN: 96360 AF XY: 0.0214

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.0307

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0205 AC: 23080 AN: 1123746 Hom.: 1 AF XY: 0.0200 AC XY: 11247 AN XY: 561392

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

African (AFR) AF: 0.0356 AC: 868 AN: 24364

American (AMR) AF: 0.0282 AC: 808 AN: 28688

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 479 AN: 19768

East Asian (EAS) AF: 0.0320 AC: 986 AN: 30778

South Asian (SAS) AF: 0.0121 AC: 824 AN: 68026

European-Finnish (FIN) AF: 0.0189 AC: 750 AN: 39632

Middle Eastern (MID) AF: 0.0301 AC: 124 AN: 4124

European-Non Finnish (NFE) AF: 0.0199 AC: 17164 AN: 862120

Other (OTH) AF: 0.0233 AC: 1077 AN: 46246

⚠️ 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: 0.000199 AC: 21 AN: 105702 Hom.: 0 Cov.: 0 AF XY: 0.000243 AC XY: 12 AN XY: 49324

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

African (AFR) AF: 0.000394 AC: 10 AN: 25352

American (AMR) AF: 0.000107 AC: 1 AN: 9346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.000924 AC: 4 AN: 4330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 202

European-Non Finnish (NFE) AF: 0.0000912 AC: 5 AN: 54810

Other (OTH) AF: 0.000697 AC: 1 AN: 1434

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000853066), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0103 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;