chr19-53634660-T-C

Position:

• chr19-53634660-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012728.2(DPRX):​c.158T>C​(p.Ile53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DPRX NM_001012728.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21303353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPRX	NM_001012728.2	c.158T>C	p.Ile53Thr	missense_variant	2/3	ENST00000376650.2	NP_001012746.1
DPRX	XM_011527011.4	c.158T>C	p.Ile53Thr	missense_variant	3/4		XP_011525313.1
DPRX	XM_011527012.3	c.158T>C	p.Ile53Thr	missense_variant	3/4		XP_011525314.1
DPRX	XM_047438893.1	c.158T>C	p.Ile53Thr	missense_variant	3/4		XP_047294849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPRX	ENST00000376650.2	c.158T>C	p.Ile53Thr	missense_variant	2/3	3	NM_001012728.2	ENSP00000365838.1
DPRX	ENST00000710707.1	c.158T>C	p.Ile53Thr	missense_variant	4/5			ENSP00000518423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Aug 20, 2024

The c.158T>C (p.I53T) alteration is located in exon 2 (coding exon 2) of the DPRX gene. This alteration results from a T to C substitution at nucleotide position 158, causing the isoleucine (I) at amino acid position 53 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	0.30
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.54	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.25
Sift	Benign	0.18	T
Sift4G	Benign	0.22	T
Polyphen		0.36	B
Vest4		0.26
MutPred		0.67		Loss of stability (P = 0.0069);
MVP		0.30
MPC		0.38
ClinPred		0.22	T
GERP RS		0.63
Varity_R		0.10
gMVP		0.29

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: rs2091105603; hg19: chr19-54137914;