5-23527530-C-G

Variant names:

• chr5-23527530-C-G
• NM_020227.4:c.2442C>G
• PRDM9 p.Ser814Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020227.4(PRDM9):​c.2442C>G​(p.Ser814Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 16)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.26
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17821717).

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.2442C>G	p.Ser814Arg	missense	Exon 11 of 11	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.2442C>G	p.Ser814Arg	missense	Exon 11 of 11	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.2442C>G	p.Ser814Arg	missense	Exon 11 of 11	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.2442C>G	p.Ser814Arg	missense	Exon 11 of 11	ENSP00000425471.2	Q9NQV7

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 108714 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 47

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 108714 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 52966

African (AFR) AF: 0.00 AC: 0 AN: 24396

American (AMR) AF: 0.00 AC: 0 AN: 11162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2932

East Asian (EAS) AF: 0.00 AC: 0 AN: 3410

South Asian (SAS) AF: 0.00 AC: 0 AN: 2934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54536

Other (OTH) AF: 0.00 AC: 0 AN: 1494

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.018
DANN	Benign	0.78
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.036	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.91	L
PhyloP100		-7.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.070
Sift	Benign	0.29	T
Sift4G	Benign	0.27	T
Varity_R		0.16
gMVP		0.020
Mutation Taster		=92/8	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-23527639;