rs1064797092

Variant names:

• chr14-58645879-G-A
• rs1064797092
• NM_001079520.2:c.1145G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001079520.2(DACT1):​c.1145G>A​(p.Trp382*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DACT1 NM_001079520.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.16
• Publications: 2 publications found

Genes affected

DACT1 (HGNC:17748): (dishevelled binding antagonist of beta catenin 1) The protein encoded by this gene belongs to the dapper family, characterized by the presence of PDZ-binding motif at the C-terminus. It interacts with, and positively regulates dishevelled-mediated signaling pathways during development. Depletion of this mRNA from xenopus embryos resulted in loss of notochord and head structures, and mice lacking this gene died shortly after birth from severe posterior malformations. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

DACT1 Gene-Disease associations (from GenCC):

• Townes-Brocks syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Townes-Brocks syndrome 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-58645879-G-A is Pathogenic according to our data. Variant chr14-58645879-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 424859.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079520.2. 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
	DACT1	NM_001079520.2	MANE Select	c.1145G>A	p.Trp382*	stop_gained	Exon 4 of 4	NP_001072988.1	Q9NYF0-2
	DACT1	NM_016651.6		c.1256G>A	p.Trp419*	stop_gained	Exon 4 of 4	NP_057735.2
	DACT1	NR_046093.2		n.925G>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT1	ENST00000395153.8	TSL:5 MANE Select	c.1145G>A	p.Trp382*	stop_gained	Exon 4 of 4	ENSP00000378582.3	Q9NYF0-2
	DACT1	ENST00000335867.4	TSL:1	c.1256G>A	p.Trp419*	stop_gained	Exon 4 of 4	ENSP00000337439.4	Q9NYF0-1
	DACT1	ENST00000707126.1		c.1145G>A	p.Trp382*	stop_gained	Exon 4 of 4	ENSP00000516754.1	Q9NYF0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251112 AF XY: 0.00000736

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Townes-Brocks syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		3.2
Vest4		0.44
GERP RS		4.5
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1064797092; hg19: chr14-59112597;