chr5-23527278-C-G

Variant names:

• chr5-23527278-C-G
• rs56256550
• NM_020227.4:c.2190C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020227.4(PRDM9):​c.2190C>G​(p.Ser730Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S730C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.61
• Publications: 4 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.236826).

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.2190C>G	p.Ser730Arg	missense	Exon 11 of 11	NP_064612.2
	PRDM9	NM_001376900.1		c.2190C>G	p.Ser730Arg	missense	Exon 11 of 11	NP_001363829.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.2190C>G	p.Ser730Arg	missense	Exon 11 of 11	ENSP00000296682.4
	PRDM9	ENST00000502755.6	TSL:4	c.2190C>G	p.Ser730Arg	missense	Exon 11 of 11	ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.00000877 AC: 1 AN: 114074 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000403

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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1381360 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 686278

African (AFR) AF: 0.00 AC: 0 AN: 28930

American (AMR) AF: 0.00 AC: 0 AN: 38748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23266

East Asian (EAS) AF: 0.00 AC: 0 AN: 34164

South Asian (SAS) AF: 0.00 AC: 0 AN: 81604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065496

Other (OTH) AF: 0.00 AC: 0 AN: 54908

GnomAD4 genome AF: 0.00000877 AC: 1 AN: 114074 Hom.: 0 Cov.: 17 AF XY: 0.0000179 AC XY: 1 AN XY: 55808

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

African (AFR) AF: 0.0000403 AC: 1 AN: 24828

American (AMR) AF: 0.00 AC: 0 AN: 11840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2982

East Asian (EAS) AF: 0.00 AC: 0 AN: 3900

South Asian (SAS) AF: 0.00 AC: 0 AN: 3284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56576

Other (OTH) AF: 0.00 AC: 0 AN: 1532

⚠️ 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.61
DANN	Benign	0.81
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.033	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.44	N
PhyloP100		-4.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.062
Sift	Benign	0.047	D
Sift4G	Benign	0.072	T
Polyphen		0.89	P
Vest4		0.13
MutPred		0.65		Gain of MoRF binding (P = 0.0176)
MVP		0.048
MPC		0.18
ClinPred		0.31	T
GERP RS		-5.6
Varity_R		0.27
gMVP		0.021
Mutation Taster		=97/3	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: rs56256550; hg19: chr5-23527387;