19-53636977-C-G

Position:

• chr19-53636977-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001012728.2(DPRX):​c.565C>G​(p.Arg189Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPRX NM_001012728.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

Genes affected

DPRX (HGNC:32166): (divergent-paired related homeobox) Homeobox genes encode DNA-binding proteins, many of which are thought to be involved in early embryonic development. Homeobox genes encode a DNA-binding domain of 60 to 63 amino acids referred to as the homeodomain. This gene is a member of the DPRX homeobox gene family. Evidence of mRNA expression has not yet been found for this gene. Multiple, related processed pseudogenes have been found which are thought to reflect expression of this gene in the germ line or embryonic cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046260983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPRX	NM_001012728.2	c.565C>G	p.Arg189Gly	missense_variant	3/3	ENST00000376650.2	NP_001012746.1
DPRX	XM_011527011.4	c.565C>G	p.Arg189Gly	missense_variant	4/4		XP_011525313.1
DPRX	XM_011527012.3	c.565C>G	p.Arg189Gly	missense_variant	4/4		XP_011525314.1
DPRX	XM_047438893.1	c.565C>G	p.Arg189Gly	missense_variant	4/4		XP_047294849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPRX	ENST00000376650.2	c.565C>G	p.Arg189Gly	missense_variant	3/3	3	NM_001012728.2	ENSP00000365838.1
DPRX	ENST00000710707.1	c.565C>G	p.Arg189Gly	missense_variant	5/5			ENSP00000518423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jul 31, 2024

The c.565C>G (p.R189G) alteration is located in exon 3 (coding exon 3) of the DPRX gene. This alteration results from a C to G substitution at nucleotide position 565, causing the arginine (R) at amino acid position 189 to be replaced by a glycine (G). 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	0.086
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.7
DANN	Benign	0.71
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.013	B
Vest4		0.17
MutPred		0.12		Loss of solvent accessibility (P = 0.0159);
MVP		0.13
MPC		0.16
ClinPred		0.068	T
GERP RS		-2.5
Varity_R		0.070
gMVP		0.11

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: rs377492034; hg19: chr19-54140231;