NM_020227.4:c.2042C>T

Variant names:

• chr5-23527130-C-T
• rs6875787
• NM_020227.4:c.2042C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):​c.2042C>T​(p.Thr681Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 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. T681S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 6)
  • Exomes 𝑓: 0.0000052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -15.7

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03910759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM9	NM_020227.4	c.2042C>T	p.Thr681Ile	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2
PRDM9	NM_001376900.1	c.2042C>T	p.Thr681Ile	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.2042C>T	p.Thr681Ile	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4
PRDM9	ENST00000502755.6	c.2042C>T	p.Thr681Ile	missense_variant	Exon 11 of 11	4		ENSP00000425471.2

Frequencies

GnomAD3 genomes Cov.: 6

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000518 AC: 2 AN: 385896 Hom.: 0 Cov.: 0 AF XY: 0.00000966 AC XY: 2 AN XY: 207122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000444

Gnomad4 OTH exome AF: 0.0000464

GnomAD4 genome Cov.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0010
DANN	Benign	0.75
DEOGEN2	Benign	0.042	T
Eigen	Benign	-3.0
Eigen_PC	Benign	-3.1
FATHMM_MKL	Benign	0.00043	N
LIST_S2	Benign	0.035	T
M_CAP	Benign	0.00062	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.012
Sift	Benign	0.33	T
Sift4G	Benign	0.34	T
Polyphen		0.025	B
Vest4		0.039
MutPred		0.48		Loss of phosphorylation at T681 (P = 0.0308);
MVP		0.12
MPC		0.19
ClinPred		0.24	T
GERP RS		-5.3
Varity_R		0.027
gMVP		0.024

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: rs6875787; hg19: chr5-23527239;