rs56256550

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-23527278-C-A
• chr5-23527278-C-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>A​(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 0.00074 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000017 (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=0.16019985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.2190C>A	p.Ser730Arg	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.2190C>A	p.Ser730Arg	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.2190C>A	p.Ser730Arg	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.2190C>A	p.Ser730Arg	missense_variant	Exon 11 of 11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.000722 AC: 82 AN: 113640 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000847

Gnomad ASJ AF: 0.000674

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.000611

Gnomad FIN AF: 0.000121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000337

Gnomad OTH AF: 0.000654

GnomAD2 exomes AF: 0.0000127 AC: 3 AN: 235942 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000167 AC: 23 AN: 1380688 Hom.: 0 Cov.: 34 AF XY: 0.0000117 AC XY: 8 AN XY: 685962

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

African (AFR) AF: 0.0000694 AC: 2 AN: 28838

American (AMR) AF: 0.0000258 AC: 1 AN: 38710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23244

East Asian (EAS) AF: 0.0000880 AC: 3 AN: 34088

South Asian (SAS) AF: 0.00 AC: 0 AN: 81578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 0.0000122 AC: 13 AN: 1065158

Other (OTH) AF: 0.0000729 AC: 4 AN: 54854

⚠️ 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 AF: 0.000739 AC: 84 AN: 113716 Hom.: 0 Cov.: 17 AF XY: 0.000754 AC XY: 42 AN XY: 55674

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

African (AFR) AF: 0.00186 AC: 46 AN: 24776

American (AMR) AF: 0.000846 AC: 10 AN: 11824

Ashkenazi Jewish (ASJ) AF: 0.000674 AC: 2 AN: 2968

East Asian (EAS) AF: 0.000776 AC: 3 AN: 3864

South Asian (SAS) AF: 0.000611 AC: 2 AN: 3274

European-Finnish (FIN) AF: 0.000121 AC: 1 AN: 8236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.000337 AC: 19 AN: 56368

Other (OTH) AF: 0.000645 AC: 1 AN: 1550

⚠️ 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: 0.0138 Hom.: 0

ExAC AF: 0.00000831 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.59
DANN	Benign	0.79
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.033	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.16	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	0.059
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		0.22	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; COSMIC: COSV57005210; COSMIC: COSV57005210;