19-46660940-T-C

Variant names:

• chr19-46660940-T-C
• rs1270574315
• NM_145056.3:c.125A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145056.3(DACT3):​c.125A>G​(p.Gln42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DACT3 NM_145056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0650
• Publications: 1 publications found

Genes affected

DACT3 (HGNC:30745): (dishevelled binding antagonist of beta catenin 3) Predicted to enable delta-catenin binding activity; protein kinase A binding activity; and protein kinase C binding activity. Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of cell growth. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DACT3-AS1 (HGNC:44120): (DACT3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06044981).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145056.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT3	NM_145056.3	MANE Select	c.125A>G	p.Gln42Arg	missense	Exon 1 of 4	NP_659493.2	Q96B18
	DACT3-AS1	NR_040042.1		n.45+532T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT3	ENST00000391916.7	TSL:5 MANE Select	c.125A>G	p.Gln42Arg	missense	Exon 1 of 4	ENSP00000375783.2	Q96B18
	DACT3	ENST00000410105.2	TSL:2	c.125A>G	p.Gln42Arg	missense	Exon 1 of 3	ENSP00000387300.1	G5E9H6
	DACT3-AS1	ENST00000525008.6	TSL:2	n.95+532T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 134070 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388012 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 684960

African (AFR) AF: 0.00 AC: 0 AN: 31240

American (AMR) AF: 0.00 AC: 0 AN: 35578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25052

East Asian (EAS) AF: 0.00 AC: 0 AN: 35544

South Asian (SAS) AF: 0.00 AC: 0 AN: 78826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1078060

Other (OTH) AF: 0.00 AC: 0 AN: 57832

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.23	N
PhyloP100		0.065
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.35	N
REVEL	Benign	0.045
Sift	Benign	0.44	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.34		Gain of MoRF binding (P = 0.0308)
MVP		0.12
ClinPred		0.072	T
GERP RS		-0.074
PromoterAI		0.13	Neutral
Varity_R		0.092
gMVP		0.27
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1270574315; hg19: chr19-47164197;