Genetic Variant PRDM9:c.301+42_301+44delTTT (chr5-23510049-ATTT-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS1

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

Variant links:

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]

PRDM9 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0205 (23080/1123746) while in subpopulation AFR AF= 0.0356 (868/24364). AF 95% confidence interval is 0.0337. There are 1 homozygotes in gnomad4_exome. There are 11247 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4 link	c.301+42_301+44delTTT		intron_variant	Intron 4 of 10	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 link	c.301+42_301+44delTTT		intron_variant	Intron 4 of 10		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRDM9	ENST00000296682.4 link	c.301+23_301+25delTTT	intron_variant	Intron 4 of 10	1	NM_020227.4	ENSP00000296682.4	Q9NQV7
PRDM9	ENST00000502755.6 link	c.301+23_301+25delTTT	intron_variant	Intron 4 of 10	4		ENSP00000425471.2	Q9NQV7D6RD68
PRDM9	ENST00000635252.1 link	c.124+23_124+25delTTT	intron_variant	Intron 4 of 10	5		ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes

AF:

0.000199

AC:

AN:

105710

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0215

AC:

2072

AN:

96360

Hom.:

AF XY:

0.0214

AC XY:

1093

AN XY:

51080

show subpopulations

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 SAS exome

AF:

0.0187

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.:

AF XY:

0.0200

AC XY:

11247

AN XY:

561392

show subpopulations

Gnomad4 AFR exome

AF:

0.0356

Gnomad4 AMR exome

AF:

0.0282

Gnomad4 ASJ exome

AF:

0.0242

Gnomad4 EAS exome

AF:

0.0320

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.0189

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0233

GnomAD4 genome

AF:

0.000199

AC:

AN:

105702

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

49324

show subpopulations

Gnomad4 AFR

AF:

0.000394

Gnomad4 AMR

AF:

0.000107

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000924

Gnomad4 NFE

AF:

0.0000912

Gnomad4 OTH

AF:

0.000697

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

5-23510049-ATTTTTTTTTTT-ATTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over