21-41815713-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001040424.3(PRDM15):c.2384G>A(p.Arg795Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRDM15 NM_001040424.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

PRDM15 (HGNC:13999): (PR/SET domain 15) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and promoter-specific chromatin binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II; regulation of signal transduction; and regulation of stem cell division. Located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRDM15

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM15	NM_001040424.3	c.2384G>A	p.Arg795Gln	missense_variant	19/24	ENST00000398548.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM15	ENST00000398548.6	c.2384G>A	p.Arg795Gln	missense_variant	19/24	1	NM_001040424.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461264 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2022

The c.3482G>A (p.R1161Q) alteration is located in exon 26 (coding exon 26) of the PRDM15 gene. This alteration results from a G to A substitution at nucleotide position 3482, causing the arginine (R) at amino acid position 1161 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.74
MutPred		0.43		.;.;.;Loss of MoRF binding (P = 0.0353);
MVP		0.71
MPC		1.4
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.84

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

Other links and lift over

dbSNP: rs1325006511; hg19: chr21-43236069;