5-23510094-A-G

Position:

• chr5-23510094-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020227.4(PRDM9):​c.301+67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,451,960 control chromosomes in the GnomAD database, including 671,563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (66328 hom., cov: 19)
  • Exomes 𝑓: 0.96 (605235 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.59

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 5-23510094-A-G is Benign according to our data. Variant chr5-23510094-A-G is described in ClinVar as [Benign]. Clinvar id is 1252878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM9	NM_020227.4	c.301+67A>G		intron_variant		ENST00000296682.4
PRDM9	NM_001376900.1	c.301+67A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM9	ENST00000296682.4	c.301+67A>G		intron_variant		1	NM_020227.4	P1
PRDM9	ENST00000502755.6	c.301+67A>G		intron_variant		4
PRDM9	ENST00000635252.1	c.124+67A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.957 AC: 138361 AN: 144514 Hom.: 66295 Cov.: 19

Gnomad AFR AF: 0.945

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.980

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.981

Gnomad MID AF: 0.964

Gnomad NFE AF: 0.965

Gnomad OTH AF: 0.974

GnomAD4 exome AF: 0.962 AC: 1257342 AN: 1307374 Hom.: 605235 AF XY: 0.962 AC XY: 626871 AN XY: 651572

Gnomad4 AFR exome AF: 0.942

Gnomad4 AMR exome AF: 0.989

Gnomad4 ASJ exome AF: 0.977

Gnomad4 EAS exome AF: 0.801

Gnomad4 SAS exome AF: 0.969

Gnomad4 FIN exome AF: 0.978

Gnomad4 NFE exome AF: 0.965

Gnomad4 OTH exome AF: 0.960

GnomAD4 genome AF: 0.957 AC: 138430 AN: 144586 Hom.: 66328 Cov.: 19 AF XY: 0.958 AC XY: 66837 AN XY: 69778

Gnomad4 AFR AF: 0.945

Gnomad4 AMR AF: 0.980

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 0.818

Gnomad4 SAS AF: 0.959

Gnomad4 FIN AF: 0.981

Gnomad4 NFE AF: 0.965

Gnomad4 OTH AF: 0.973

Alfa AF: 0.949 Hom.: 7024

Asia WGS AF: 0.916 AC: 3183 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.58
DANN	Benign	0.37

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

Other links and lift over

dbSNP: rs2973615; hg19: chr5-23510203;