5-23527279-A-T

Variant names:

• chr5-23527279-A-T
• rs58979818
• NM_020227.4:c.2191A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020227.4(PRDM9):​c.2191A>T​(p.Asn731Tyr) 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.

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM9 NM_020227.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.09
• Publications: 6 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=0.04417619).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	NM_020227.4	MANE Select	c.2191A>T	p.Asn731Tyr	missense	Exon 11 of 11	NP_064612.2
	PRDM9	NM_001376900.1		c.2191A>T	p.Asn731Tyr	missense	Exon 11 of 11	NP_001363829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM9	ENST00000296682.4	TSL:1 MANE Select	c.2191A>T	p.Asn731Tyr	missense	Exon 11 of 11	ENSP00000296682.4
	PRDM9	ENST00000502755.6	TSL:4	c.2191A>T	p.Asn731Tyr	missense	Exon 11 of 11	ENSP00000425471.2

Frequencies

GnomAD3 genomes AF: 0.0000467 AC: 2 AN: 42796 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000110

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: 0.0000456

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000168 AC: 2 AN: 1187020 Hom.: 0 Cov.: 35 AF XY: 0.00000170 AC XY: 1 AN XY: 588776

⚠️ 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: 24422

American (AMR) AF: 0.00 AC: 0 AN: 30894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17454

East Asian (EAS) AF: 0.00 AC: 0 AN: 18444

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4516

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 938448

Other (OTH) AF: 0.00 AC: 0 AN: 43934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000467 AC: 2 AN: 42824 Hom.: 0 Cov.: 0 AF XY: 0.0000937 AC XY: 2 AN XY: 21350

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

African (AFR) AF: 0.000110 AC: 1 AN: 9068

American (AMR) AF: 0.00 AC: 0 AN: 4382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1144

East Asian (EAS) AF: 0.00 AC: 0 AN: 1386

South Asian (SAS) AF: 0.00 AC: 0 AN: 1192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 62

European-Non Finnish (NFE) AF: 0.0000456 AC: 1 AN: 21936

Other (OTH) AF: 0.00 AC: 0 AN: 604

⚠️ 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: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.29
DANN	Benign	0.51
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.068	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		-4.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.0080
Sift	Benign	0.95	T
Sift4G	Benign	0.25	T
Polyphen		0.0090	B
Vest4		0.074
MutPred		0.48		Gain of phosphorylation at N731 (P = 0.0579)
MVP		0.048
MPC		0.20
ClinPred		0.034	T
GERP RS		-2.1
Varity_R		0.059
gMVP		0.040
Mutation Taster		=98/2	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: rs58979818; hg19: chr5-23527388; COSMIC: COSV104393166; COSMIC: COSV104393166;