Genetic Variant PRDM9:p.Thr681Ile (chr5-23527130-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -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. 15/22 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. 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -15.7

Publications

14 publications found

Variant links:

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]

PRDM9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 link	c.2042C>T	p.Thr681Ile	missense_variant	Exon 11 of 11	ENST00000296682.4	NP_064612.2	Q9NQV7
PRDM9	NM_001376900.1 link	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 link	c.2042C>T	p.Thr681Ile	missense_variant	Exon 11 of 11	1	NM_020227.4	ENSP00000296682.4		Q9NQV7
PRDM9	ENST00000502755.6 link	c.2042C>T	p.Thr681Ile	missense_variant	Exon 11 of 11	4		ENSP00000425471.2		Q9NQV7D6RD68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000518

AC:

AN:

385896

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

207122

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

10310

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10812

East Asian (EAS)

AF:

0.00

AC:

AN:

26868

South Asian (SAS)

AF:

0.00

AC:

AN:

36046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3032

European-Non Finnish (NFE)

AF:

0.00000444

AC:

AN:

225308

Other (OTH)

AF:

0.0000464

AC:

AN:

21548

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0010

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.042

Eigen

Benign

-3.0

Eigen_PC

Benign

-3.1

FATHMM_MKL

Benign

0.00043

LIST_S2

Benign

0.035

M_CAP

Benign

0.00062

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-16

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.97

REVEL

Benign

0.012

Sift

Benign

0.33

Sift4G

Benign

0.34

Polyphen

0.025

Vest4

0.039

MutPred

0.48

Loss of phosphorylation at T681 (P = 0.0308);

MVP

0.12

MPC

0.19

ClinPred

0.24

GERP RS

-5.3

Varity_R

0.027

gMVP

0.024

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over