5-23510049-ATTTTTTTTTTT-ATTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020227.4(PRDM9):​c.301+43_301+44delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,199,738 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (25 hom., cov: 0)
  • Exomes 𝑓: 0.13 (12 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-23510049-ATT-A is Benign according to our data. Variant chr5-23510049-ATT-A is described in ClinVar as Benign. ClinVar VariationId is 1295150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.026 (2743/105688) while in subpopulation AFR AF = 0.0476 (1208/25364). AF 95% confidence interval is 0.0454. There are 25 homozygotes in GnomAd4. There are 1240 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

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+44delTT		intron	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.301+43_301+44delTT		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+24delTT		intron	N/A	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.301+23_301+24delTT		intron	N/A	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.124+23_124+24delTT		intron	N/A	ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 2743 AN: 105696 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.00839

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.0324

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0338

GnomAD2 exomes AF: 0.138 AC: 13301 AN: 96360 AF XY: 0.133

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.0631

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.129 AC: 141083 AN: 1094050 Hom.: 12 AF XY: 0.128 AC XY: 69873 AN XY: 544950

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

African (AFR) AF: 0.194 AC: 4665 AN: 24104

American (AMR) AF: 0.162 AC: 4505 AN: 27818

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 2558 AN: 19118

East Asian (EAS) AF: 0.156 AC: 4690 AN: 30046

South Asian (SAS) AF: 0.127 AC: 8119 AN: 63682

European-Finnish (FIN) AF: 0.107 AC: 4082 AN: 38058

Middle Eastern (MID) AF: 0.139 AC: 563 AN: 4050

European-Non Finnish (NFE) AF: 0.125 AC: 105594 AN: 842038

Other (OTH) AF: 0.140 AC: 6307 AN: 45136

⚠️ 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: 0.0260 AC: 2743 AN: 105688 Hom.: 25 Cov.: 0 AF XY: 0.0251 AC XY: 1240 AN XY: 49314

African (AFR) AF: 0.0476 AC: 1208 AN: 25364

American (AMR) AF: 0.0220 AC: 206 AN: 9344

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 130 AN: 2878

East Asian (EAS) AF: 0.0360 AC: 131 AN: 3634

South Asian (SAS) AF: 0.00846 AC: 25 AN: 2956

European-Finnish (FIN) AF: 0.00623 AC: 27 AN: 4332

Middle Eastern (MID) AF: 0.0350 AC: 7 AN: 200

European-Non Finnish (NFE) AF: 0.0172 AC: 942 AN: 54794

Other (OTH) AF: 0.0335 AC: 48 AN: 1432

Alfa AF: 0.0572 Hom.: 179

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;