rs61051796

Variant names:

• chr5-23527528-A-C
• rs61051796
• NM_020227.4:c.2440A>C

Variant summary

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

The NM_020227.4(PRDM9):​c.2440A>C​(p.Ser814Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.0036 (0 hom., cov: 16)
  • Exomes 𝑓: 0.00019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220

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=0.004315704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.2440A>C	p.Ser814Arg	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.2440A>C	p.Ser814Arg	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.2440A>C	p.Ser814Arg	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.2440A>C	p.Ser814Arg	missense_variant	Exon 11 of 11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 357 AN: 101662 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.0135

Gnomad AMR AF: 0.00257

Gnomad ASJ AF: 0.000721

Gnomad EAS AF: 0.00142

Gnomad SAS AF: 0.000678

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00554

GnomAD2 exomes AF: 0.000624 AC: 145 AN: 232206 AF XY: 0.000432

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.000167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000357

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.000697

Gnomad OTH exome AF: 0.000895

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000189 AC: 266 AN: 1410482 Hom.: 0 Cov.: 49 AF XY: 0.000242 AC XY: 170 AN XY: 701214

Gnomad4 AFR exome AF: 0.00111 AC: 28 AN: 25158

Gnomad4 AMR exome AF: 0.000266 AC: 11 AN: 41390

Gnomad4 ASJ exome AF: 0.0000402 AC: 1 AN: 24874

Gnomad4 EAS exome AF: 0.000189 AC: 7 AN: 37086

Gnomad4 SAS exome AF: 0.000148 AC: 12 AN: 81046

Gnomad4 FIN exome AF: 0.000267 AC: 14 AN: 52482

Gnomad4 NFE exome AF: 0.000132 AC: 143 AN: 1086624

Gnomad4 Remaining exome AF: 0.000371 AC: 21 AN: 56642

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00357 AC: 363 AN: 101722 Hom.: 0 Cov.: 16 AF XY: 0.00325 AC XY: 161 AN XY: 49482

Gnomad4 AFR AF: 0.0128 AC: 0.0127928 AN: 0.0127928

Gnomad4 AMR AF: 0.00266 AC: 0.00266059 AN: 0.00266059

Gnomad4 ASJ AF: 0.000721 AC: 0.000720981 AN: 0.000720981

Gnomad4 EAS AF: 0.00170 AC: 0.00170455 AN: 0.00170455

Gnomad4 SAS AF: 0.000682 AC: 0.000681663 AN: 0.000681663

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00134 AC: 0.00134143 AN: 0.00134143

Gnomad4 OTH AF: 0.00549 AC: 0.00548697 AN: 0.00548697

Alfa AF: 0.0609 Hom.: 0

ESP6500AA AF: 0.00398 AC: 17

ESP6500EA AF: 0.000352 AC: 3

ExAC AF: 0.000853 AC: 103

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.0
DANN	Benign	0.84
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.036	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.91	L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.094
Sift	Benign	0.29	T
Sift4G	Benign	0.27	T
Polyphen		0.79	P
Vest4		0.12
MutPred		0.59		Gain of MoRF binding (P = 0.0186);
MVP		0.21
MPC		0.37
ClinPred		0.0084	T
GERP RS		3.0
Varity_R		0.16
gMVP		0.020
Mutation Taster		=86/14	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

Publications

LitVar

Other links and lift over

dbSNP: rs61051796; hg19: chr5-23527637; COSMIC: COSV57001900; COSMIC: COSV57001900;