21-41801512-C-T

Variant names:

• chr21-41801512-C-T
• rs1407131702
• NM_001040424.3:c.3154G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001040424.3(PRDM15):​c.3154G>A​(p.Ala1052Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRDM15 NM_001040424.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32132024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM15	NM_001040424.3	c.3154G>A	p.Ala1052Thr	missense_variant	Exon 24 of 24	ENST00000398548.6	NP_001035514.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM15	ENST00000398548.6	c.3154G>A	p.Ala1052Thr	missense_variant	Exon 24 of 24	1	NM_001040424.3	ENSP00000381556.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4252G>A (p.A1418T) alteration is located in exon 31 (coding exon 31) of the PRDM15 gene. This alteration results from a G to A substitution at nucleotide position 4252, causing the alanine (A) at amino acid position 1418 to be replaced by a threonine (T). 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	Benign	0.26
BayesDel_addAF	Benign	-0.0069	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	.;.;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.34
MutPred		0.23		.;.;.;Gain of disorder (P = 0.0826);
MVP		0.093
MPC		1.2
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.11
gMVP		0.66

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: rs1407131702; hg19: chr21-43221672;