rs55862350

Variant names:

• chr5-23527373-A-T
• rs55862350
• NM_020227.4:c.2285A>T

Your query was ambiguous. Multiple possible variants found:

• chr5-23527373-A-T
• chr5-23527373-A-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.2285A>T​(p.His762Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 10)
  • Exomes 𝑓: 0.0000059 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044679046).

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.2285A>T	p.His762Leu	missense	Exon 11 of 11	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.2285A>T	p.His762Leu	missense	Exon 11 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.2285A>T	p.His762Leu	missense	Exon 11 of 11	ENSP00000296682.4	Q9NQV7
	PRDM9	ENST00000502755.6	TSL:4	c.2285A>T	p.His762Leu	missense	Exon 11 of 11	ENSP00000425471.2	Q9NQV7

Frequencies

GnomAD3 genomes AF: 0.0000351 AC: 2 AN: 56956 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.000202

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000426 AC: 1 AN: 234904 AF XY: 0.00000779

Gnomad AFR exome AF: 0.0000812

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000594 AC: 8 AN: 1347588 Hom.: 0 Cov.: 37 AF XY: 0.00000896 AC XY: 6 AN XY: 669974

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

African (AFR) AF: 0.0000775 AC: 2 AN: 25806

American (AMR) AF: 0.0000264 AC: 1 AN: 37930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21572

East Asian (EAS) AF: 0.0000317 AC: 1 AN: 31520

South Asian (SAS) AF: 0.00 AC: 0 AN: 81458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4886

European-Non Finnish (NFE) AF: 0.00000287 AC: 3 AN: 1044574

Other (OTH) AF: 0.0000192 AC: 1 AN: 51964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000606578), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000351 AC: 2 AN: 56956 Hom.: 0 Cov.: 10 AF XY: 0.0000713 AC XY: 2 AN XY: 28056

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

African (AFR) AF: 0.000202 AC: 2 AN: 9878

American (AMR) AF: 0.00 AC: 0 AN: 4896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1718

East Asian (EAS) AF: 0.00 AC: 0 AN: 1892

South Asian (SAS) AF: 0.00 AC: 0 AN: 1366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32834

Other (OTH) AF: 0.00 AC: 0 AN: 774

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000547 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.014
DANN	Benign	0.24
DEOGEN2	Benign	0.094	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.92	L
PhyloP100		-1.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.028
Sift	Benign	0.36	T
Sift4G	Benign	0.32	T
Polyphen		0.0070	B
Vest4		0.14
MVP		0.048
MPC		0.16
ClinPred		0.067	T
GERP RS		-5.9
Varity_R		0.26
gMVP		0.066
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs55862350; hg19: chr5-23527482; COSMIC: COSV57002796; COSMIC: COSV57002796;