19-57160776-C-G

Position:

• chr19-57160776-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012729.2(DUXA):​c.47G>C​(p.Arg16Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DUXA NM_001012729.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

Genes affected

DUXA (HGNC:32179): (double homeobox A) 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 DUXA 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUXA	NM_001012729.2	c.47G>C	p.Arg16Thr	missense_variant	2/6	ENST00000554048.3	NP_001012747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUXA	ENST00000554048.3	c.47G>C	p.Arg16Thr	missense_variant	2/6	3	NM_001012729.2	ENSP00000452398.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 09, 2023

The c.47G>C (p.R16T) alteration is located in exon 2 (coding exon 2) of the DUXA gene. This alteration results from a G to C substitution at nucleotide position 47, causing the arginine (R) at amino acid position 16 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	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.97	D
Vest4		0.63
MutPred		0.67		Loss of MoRF binding (P = 0.0205);
MVP		0.85
MPC		0.82
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.42
gMVP		0.42

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: chr19-57672144;