5-23517916-C-A

Variant names:

• chr5-23517916-C-A
• rs62342743
• NM_020227.4:c.337C>A

Variant summary

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

The NM_020227.4(PRDM9):​c.337C>A​(p.Arg113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,599,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 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. R113C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.888
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.337C>A	p.Arg113Ser	missense	Exon 5 of 11	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.337C>A	p.Arg113Ser	missense	Exon 5 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.337C>A	p.Arg113Ser	missense	Exon 5 of 11	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.337C>A	p.Arg113Ser	missense	Exon 5 of 11	ENSP00000425471.2	Q9NQV7
	PRDM9	ENST00000635252.1	TSL:5	c.160C>A	p.Arg54Ser	missense	Exon 5 of 11	ENSP00000489227.1	A0A0U1RQY2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000553 AC: 8 AN: 1447406 Hom.: 0 Cov.: 30 AF XY: 0.00000694 AC XY: 5 AN XY: 720928

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

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000728 AC: 8 AN: 1098886

Other (OTH) AF: 0.00 AC: 0 AN: 59922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000459745), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.19
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00014	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.00072	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.090	N
PhyloP100		0.89
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.074
MutPred		0.24		Gain of ubiquitination at K117 (P = 0.0326)
MVP		0.26
MPC		0.14
ClinPred		0.022	T
GERP RS		1.7
Varity_R		0.068
gMVP		0.039
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62342743; hg19: chr5-23518025; COSMIC: COSV57005266;