21-41801698-T-G

Position:

• chr21-41801698-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001040424.3(PRDM15):​c.2968A>C​(p.Asn990His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 7.40

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
• PP2: Missense variant where missense usually causes diseases, PRDM15
• BP4: Computational evidence support a benign effect (MetaRNN=0.16821277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM15	NM_001040424.3	c.2968A>C	p.Asn990His	missense_variant	24/24	ENST00000398548.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM15	ENST00000398548.6	c.2968A>C	p.Asn990His	missense_variant	24/24	1	NM_001040424.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

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

Sep 14, 2023

The c.4066A>C (p.N1356H) alteration is located in exon 31 (coding exon 31) of the PRDM15 gene. This alteration results from a A to C substitution at nucleotide position 4066, causing the asparagine (N) at amino acid position 1356 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.95
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.98	.;.;.;D
Vest4		0.24
MutPred		0.20		.;.;.;Loss of loop (P = 0.0235);
MVP		0.24
MPC		0.46
ClinPred		0.45	T
GERP RS		3.3
Varity_R		0.098
gMVP		0.56

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: chr21-43221858;