21-41801245-A-T

Variant summary

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

The NM_001040424.3(PRDM15):c.3421T>A(p.Tyr1141Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM15 NM_001040424.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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.3421T>A	p.Tyr1141Asn	missense_variant	24/24	ENST00000398548.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM15	ENST00000398548.6	c.3421T>A	p.Tyr1141Asn	missense_variant	24/24	1	NM_001040424.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Nov 28, 2023

The c.4519T>A (p.Y1507N) alteration is located in exon 31 (coding exon 31) of the PRDM15 gene. This alteration results from a T to A substitution at nucleotide position 4519, causing the tyrosine (Y) at amino acid position 1507 to be replaced by an asparagine (N). 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	0.80
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Benign	0.97
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.69
MutPred		0.29		.;.;.;Loss of phosphorylation at Y1507 (P = 0.0525);
MVP		0.20
MPC		1.1
ClinPred		0.85	D
GERP RS		4.6
Varity_R		0.36
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-43221405;