NM_020227.4:c.301+44delT

Variant names:

• chr5-23510049-AT-A
• rs34033521
• NM_020227.4:c.301+44delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_020227.4(PRDM9):​c.301+44delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (5407 hom., cov: 0)
  • Exomes 𝑓: 0.33 (648 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-23510049-AT-A is Benign according to our data. Variant chr5-23510049-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1249566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.354 AC: 37408 AN: 105682 Hom.: 5401 Cov.: 0

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.256 AC: 24687 AN: 96360 AF XY: 0.252

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.288

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.276

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.326 AC: 366281 AN: 1122686 Hom.: 648 Cov.: 0 AF XY: 0.325 AC XY: 181923 AN XY: 560120

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

African (AFR) AF: 0.360 AC: 8947 AN: 24828

American (AMR) AF: 0.307 AC: 8951 AN: 29122

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 5420 AN: 19530

East Asian (EAS) AF: 0.317 AC: 9938 AN: 31366

South Asian (SAS) AF: 0.326 AC: 21881 AN: 67034

European-Finnish (FIN) AF: 0.275 AC: 10602 AN: 38486

Middle Eastern (MID) AF: 0.302 AC: 1248 AN: 4130

European-Non Finnish (NFE) AF: 0.330 AC: 284172 AN: 861778

Other (OTH) AF: 0.326 AC: 15122 AN: 46412

⚠️ 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: 0.354 AC: 37414 AN: 105674 Hom.: 5407 Cov.: 0 AF XY: 0.349 AC XY: 17230 AN XY: 49318

African (AFR) AF: 0.477 AC: 12094 AN: 25356

American (AMR) AF: 0.377 AC: 3519 AN: 9338

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 811 AN: 2868

East Asian (EAS) AF: 0.328 AC: 1195 AN: 3640

South Asian (SAS) AF: 0.328 AC: 970 AN: 2956

European-Finnish (FIN) AF: 0.243 AC: 1053 AN: 4338

Middle Eastern (MID) AF: 0.223 AC: 45 AN: 202

European-Non Finnish (NFE) AF: 0.310 AC: 16985 AN: 54786

Other (OTH) AF: 0.333 AC: 478 AN: 1434

Alfa AF: 0.192 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		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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;