5-23526794-T-G

Variant names:

• chr5-23526794-T-G
• rs772744700
• NM_020227.4:c.1706T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):​c.1706T>G​(p.Ile569Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I569N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -9.39
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020576656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.1706T>G	p.Ile569Ser	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.1706T>G	p.Ile569Ser	missense_variant	Exon 11 of 11		NP_001363829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM9	ENST00000296682.4	c.1706T>G	p.Ile569Ser	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.1706T>G	p.Ile569Ser	missense_variant	Exon 11 of 11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 22 AN: 98416 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000777

Gnomad AMI AF: 0.00206

Gnomad AMR AF: 0.0000957

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000728

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.000619

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000174

Gnomad OTH AF: 0.000709

GnomAD2 exomes AF: 0.00000496 AC: 1 AN: 201690 AF XY: 0.00000899

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000493 AC: 58 AN: 1176296 Hom.: 0 Cov.: 36 AF XY: 0.0000446 AC XY: 26 AN XY: 582620

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

African (AFR) AF: 0.0000862 AC: 2 AN: 23198

American (AMR) AF: 0.0000343 AC: 1 AN: 29192

Ashkenazi Jewish (ASJ) AF: 0.000186 AC: 3 AN: 16100

East Asian (EAS) AF: 0.000916 AC: 12 AN: 13102

South Asian (SAS) AF: 0.00 AC: 0 AN: 74694

European-Finnish (FIN) AF: 0.0000872 AC: 3 AN: 34414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.0000362 AC: 34 AN: 938906

Other (OTH) AF: 0.0000709 AC: 3 AN: 42306

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000223 AC: 22 AN: 98482 Hom.: 0 Cov.: 29 AF XY: 0.000204 AC XY: 10 AN XY: 48940

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

African (AFR) AF: 0.0000775 AC: 2 AN: 25808

American (AMR) AF: 0.0000957 AC: 1 AN: 10450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2454

East Asian (EAS) AF: 0.000728 AC: 2 AN: 2746

South Asian (SAS) AF: 0.00112 AC: 3 AN: 2684

European-Finnish (FIN) AF: 0.000619 AC: 4 AN: 6458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 126

European-Non Finnish (NFE) AF: 0.000174 AC: 8 AN: 45850

Other (OTH) AF: 0.000704 AC: 1 AN: 1420

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000602 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.078
DANN	Benign	0.31
DEOGEN2	Benign	0.046	T
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.00076	N
LIST_S2	Benign	0.037	T
M_CAP	Benign	0.00078	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.38	N
PhyloP100		-9.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.0070
Sift	Benign	0.81	T
Sift4G	Benign	0.76	T
Vest4		0.030
ClinPred		0.041	T
GERP RS		-4.6
Varity_R		0.040
gMVP		0.033
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs772744700; hg19: chr5-23526903;