5-23523239-C-T

Variant names:

• chr5-23523239-C-T
• rs1874165
• NM_020227.4:c.883-52C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020227.4(PRDM9):​c.883-52C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 1,565,218 control chromosomes in the GnomAD database, including 655,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54680 hom., cov: 32)
  • Exomes 𝑓: 0.92 (600745 hom.)
• Consequence: PRDM9 NM_020227.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.121
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-23523239-C-T is Benign according to our data. Variant chr5-23523239-C-T is described in ClinVar as [Benign]. Clinvar id is 1278507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.883-52C>T		intron_variant	Intron 8 of 10	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.883-52C>T		intron_variant	Intron 8 of 10		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.883-52C>T		intron_variant	Intron 8 of 10	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.883-52C>T		intron_variant	Intron 8 of 10	4		ENSP00000425471.2
PRDM9	ENST00000635252.1	c.706-52C>T		intron_variant	Intron 8 of 10	5		ENSP00000489227.1

Frequencies

GnomAD3 genomes AF: 0.836 AC: 127098 AN: 152002 Hom.: 54680 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.869

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.901

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.934

Gnomad OTH AF: 0.860

GnomAD4 exome AF: 0.920 AC: 1299926 AN: 1413098 Hom.: 600745 Cov.: 31 AF XY: 0.921 AC XY: 649578 AN XY: 705558

African (AFR) AF: 0.607 AC: 19588 AN: 32264

American (AMR) AF: 0.911 AC: 40629 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.924 AC: 23871 AN: 25828

East Asian (EAS) AF: 0.740 AC: 29185 AN: 39462

South Asian (SAS) AF: 0.910 AC: 77503 AN: 85212

European-Finnish (FIN) AF: 0.969 AC: 51705 AN: 53384

Middle Eastern (MID) AF: 0.871 AC: 4932 AN: 5664

European-Non Finnish (NFE) AF: 0.936 AC: 999814 AN: 1067838

Other (OTH) AF: 0.896 AC: 52699 AN: 58826

GnomAD4 genome AF: 0.836 AC: 127135 AN: 152120 Hom.: 54680 Cov.: 32 AF XY: 0.839 AC XY: 62380 AN XY: 74386

African (AFR) AF: 0.616 AC: 25527 AN: 41440

American (AMR) AF: 0.881 AC: 13469 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3184 AN: 3470

East Asian (EAS) AF: 0.753 AC: 3875 AN: 5144

South Asian (SAS) AF: 0.900 AC: 4333 AN: 4814

European-Finnish (FIN) AF: 0.974 AC: 10348 AN: 10628

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.934 AC: 63536 AN: 68020

Other (OTH) AF: 0.858 AC: 1813 AN: 2114

Alfa AF: 0.911 Hom.: 86305

Bravo AF: 0.819

Asia WGS AF: 0.788 AC: 2742 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.6
DANN	Benign	0.79
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1874165; hg19: chr5-23523348; COSMIC: COSV57005608;