rs2973631

Variant names:

• chr5-23528117-C-T
• rs2973631
• NM_020227.4:c.*344C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-23528117-C-T
• chr5-23528117-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020227.4(PRDM9):​c.*344C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 390,900 control chromosomes in the GnomAD database, including 1,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (1478 hom., cov: 32)
  • Exomes 𝑓: 0.045 (496 hom.)
• Consequence: PRDM9 NM_020227.4 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.684
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-23528117-C-T is Benign according to our data. Variant chr5-23528117-C-T is described in ClinVar as Benign. ClinVar VariationId is 1180241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

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.*344C>T		downstream_gene	N/A	NP_064612.2	Q9NQV7
	PRDM9	NM_001376900.1		c.*344C>T		downstream_gene	N/A	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.*344C>T		downstream_gene	N/A	ENSP00000296682.4	Q9NQV7

Frequencies

GnomAD3 genomes AF: 0.0985 AC: 14955 AN: 151874 Hom.: 1465 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.0564

Gnomad FIN AF: 0.00822

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0939

GnomAD4 exome AF: 0.0452 AC: 10793 AN: 238908 Hom.: 496 Cov.: 0 AF XY: 0.0459 AC XY: 5882 AN XY: 128118

African (AFR) AF: 0.246 AC: 1784 AN: 7240

American (AMR) AF: 0.0819 AC: 1002 AN: 12230

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 288 AN: 6460

East Asian (EAS) AF: 0.0502 AC: 605 AN: 12040

South Asian (SAS) AF: 0.0560 AC: 2090 AN: 37292

European-Finnish (FIN) AF: 0.00988 AC: 101 AN: 10222

Middle Eastern (MID) AF: 0.0714 AC: 66 AN: 924

European-Non Finnish (NFE) AF: 0.0299 AC: 4184 AN: 139846

Other (OTH) AF: 0.0532 AC: 673 AN: 12654

GnomAD4 genome AF: 0.0988 AC: 15010 AN: 151992 Hom.: 1478 Cov.: 32 AF XY: 0.0970 AC XY: 7208 AN XY: 74284

African (AFR) AF: 0.255 AC: 10564 AN: 41374

American (AMR) AF: 0.0892 AC: 1363 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.0481 AC: 248 AN: 5152

South Asian (SAS) AF: 0.0565 AC: 272 AN: 4816

European-Finnish (FIN) AF: 0.00822 AC: 87 AN: 10586

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2006 AN: 68004

Other (OTH) AF: 0.0938 AC: 198 AN: 2110

Alfa AF: 0.0587 Hom.: 182

Bravo AF: 0.112

Asia WGS AF: 0.0980 AC: 342 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.1
DANN	Benign	0.38
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs2973631; hg19: chr5-23528226;