chr1-1336134-GCCACGAGTCACATGATGT-G

Variant names:

• chr1-1336134-GCCACGAGTCACATGATGT-G
• rs1643562079
• NM_001330311.2:c.2078_*7delACATCATGTGACTCGTGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001330311.2(DVL1):​c.2078_*7delACATCATGTGACTCGTGG​(p.Asp693_Ter696delins???) variant causes a stop lost, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DVL1 NM_001330311.2 stop_lost, conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71
• Publications: 0 publications found

Genes affected

DVL1 (HGNC:3084): (dishevelled segment polarity protein 1) DVL1, the human homolog of the Drosophila dishevelled gene (dsh) encodes a cytoplasmic phosphoprotein that regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification. DVL1 is a candidate gene for neuroblastomatous transformation. The Schwartz-Jampel syndrome and Charcot-Marie-Tooth disease type 2A have been mapped to the same region as DVL1. The phenotypes of these diseases may be consistent with defects which might be expected from aberrant expression of a DVL gene during development. [provided by RefSeq, Jul 2008]

DVL1 Gene-Disease associations (from GenCC):

• autosomal dominant Robinow syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant Robinow syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330311.2. 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
	DVL1	NM_001330311.2	MANE Select	c.2078_*7delACATCATGTGACTCGTGG	p.Asp693_Ter696delins???	stop_lost conservative_inframe_deletion	Exon 15 of 15	NP_001317240.1	O14640-1
	DVL1	NM_001330311.2	MANE Select	c.2078_*7delACATCATGTGACTCGTGG		3_prime_UTR	Exon 15 of 15	NP_001317240.1	O14640-1
	DVL1	NM_004421.3		c.2003_*7delACATCATGTGACTCGTGG	p.Asp668_Ter671delins???	stop_lost conservative_inframe_deletion	Exon 15 of 15	NP_004412.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DVL1	ENST00000378888.10	TSL:5 MANE Select	c.2078_*7delACATCATGTGACTCGTGG	p.Asp693_Ter696delins???	stop_lost conservative_inframe_deletion	Exon 15 of 15	ENSP00000368166.5	O14640-1
	DVL1	ENST00000378891.9	TSL:1	c.2003_*7delACATCATGTGACTCGTGG	p.Asp668_Ter671delins???	stop_lost conservative_inframe_deletion	Exon 15 of 15	ENSP00000368169.5	O14640-2
	DVL1	ENST00000378888.10	TSL:5 MANE Select	c.2078_*7delACATCATGTGACTCGTGG		3_prime_UTR	Exon 15 of 15	ENSP00000368166.5	O14640-1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant Robinow syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1643562079; hg19: chr1-1271514;