rs77287813

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020227.4(PRDM9):​c.2368A>C​(p.Asn790His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,436,540 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.017 ( 25 hom., cov: 18)
Exomes 𝑓: 0.022 ( 429 hom. )

Consequence

PRDM9
NM_020227.4 missense

Scores

1
17

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0027828813).
BP6
Variant 5-23527456-A-C is Benign according to our data. Variant chr5-23527456-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 436412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.017 (1711/100384) while in subpopulation AMR AF= 0.0239 (200/8380). AF 95% confidence interval is 0.0212. There are 25 homozygotes in gnomad4. There are 845 alleles in male gnomad4 subpopulation. Median coverage is 18. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRDM9NM_020227.4 linkc.2368A>C p.Asn790His missense_variant Exon 11 of 11 ENST00000296682.4 NP_064612.2 Q9NQV7
PRDM9NM_001376900.1 linkc.2368A>C p.Asn790His missense_variant Exon 11 of 11 NP_001363829.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRDM9ENST00000296682.4 linkc.2368A>C p.Asn790His missense_variant Exon 11 of 11 1 NM_020227.4 ENSP00000296682.4 Q9NQV7
PRDM9ENST00000502755.6 linkc.2368A>C p.Asn790His missense_variant Exon 11 of 11 4 ENSP00000425471.2 Q9NQV7D6RD68

Frequencies

GnomAD3 genomes
AF:
0.0171
AC:
1713
AN:
100376
Hom.:
25
Cov.:
18
show subpopulations
Gnomad AFR
AF:
0.00856
Gnomad AMI
AF:
0.0149
Gnomad AMR
AF:
0.0241
Gnomad ASJ
AF:
0.0249
Gnomad EAS
AF:
0.000607
Gnomad SAS
AF:
0.00380
Gnomad FIN
AF:
0.0235
Gnomad MID
AF:
0.0323
Gnomad NFE
AF:
0.0199
Gnomad OTH
AF:
0.0268
GnomAD3 exomes
AF:
0.0232
AC:
4974
AN:
213972
Hom.:
56
AF XY:
0.0229
AC XY:
2681
AN XY:
117326
show subpopulations
Gnomad AFR exome
AF:
0.0183
Gnomad AMR exome
AF:
0.0197
Gnomad ASJ exome
AF:
0.0369
Gnomad EAS exome
AF:
0.00249
Gnomad SAS exome
AF:
0.00588
Gnomad FIN exome
AF:
0.0348
Gnomad NFE exome
AF:
0.0284
Gnomad OTH exome
AF:
0.0260
GnomAD4 exome
AF:
0.0221
AC:
29502
AN:
1336156
Hom.:
429
Cov.:
40
AF XY:
0.0220
AC XY:
14663
AN XY:
665838
show subpopulations
Gnomad4 AFR exome
AF:
0.0219
Gnomad4 AMR exome
AF:
0.0249
Gnomad4 ASJ exome
AF:
0.0409
Gnomad4 EAS exome
AF:
0.00299
Gnomad4 SAS exome
AF:
0.00810
Gnomad4 FIN exome
AF:
0.0245
Gnomad4 NFE exome
AF:
0.0230
Gnomad4 OTH exome
AF:
0.0244
GnomAD4 genome
AF:
0.0170
AC:
1711
AN:
100384
Hom.:
25
Cov.:
18
AF XY:
0.0179
AC XY:
845
AN XY:
47242
show subpopulations
Gnomad4 AFR
AF:
0.00856
Gnomad4 AMR
AF:
0.0239
Gnomad4 ASJ
AF:
0.0249
Gnomad4 EAS
AF:
0.000608
Gnomad4 SAS
AF:
0.00381
Gnomad4 FIN
AF:
0.0235
Gnomad4 NFE
AF:
0.0199
Gnomad4 OTH
AF:
0.0267
Alfa
AF:
0.00540
Hom.:
1
TwinsUK
AF:
0.0477
AC:
177
ALSPAC
AF:
0.0506
AC:
195
ExAC
AF:
0.0234
AC:
2831

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Aug 19, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.75
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
0.063
DANN
Benign
0.46
DEOGEN2
Benign
0.098
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.027
T
MetaRNN
Benign
0.0028
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.027
Sift
Benign
0.12
T
Sift4G
Benign
0.81
T
Polyphen
0.050
B
Vest4
0.099
MPC
0.13
ClinPred
0.0058
T
GERP RS
-6.2
Varity_R
0.14
gMVP
0.030

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs77287813; hg19: chr5-23527565; COSMIC: COSV57003450; COSMIC: COSV57003450; API