1-1336134-GCCACGAGTCACATGATGT-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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. 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DVL1	NM_001330311.2	c.2078_*7delACATCATGTGACTCGTGG	p.Asp693_Ter696delins???	stop_lost, conservative_inframe_deletion	Exon 15 of 15	ENST00000378888.10	NP_001317240.1
DVL1	NM_001330311.2	c.2065_*7delACATCATGTGACTCGTGG		3_prime_UTR_variant	Exon 15 of 15	ENST00000378888.10	NP_001317240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DVL1	ENST00000378888.10	c.2078_*7delACATCATGTGACTCGTGG	p.Asp693_Ter696delins???	stop_lost, conservative_inframe_deletion	Exon 15 of 15	5	NM_001330311.2	ENSP00000368166.5
DVL1	ENST00000378891.9	c.2003_*7delACATCATGTGACTCGTGG	p.Asp668_Ter671delins???	stop_lost, conservative_inframe_deletion	Exon 15 of 15	1		ENSP00000368169.5
DVL1	ENST00000378888	c.2065_*7delACATCATGTGACTCGTGG		3_prime_UTR_variant	Exon 15 of 15	5	NM_001330311.2	ENSP00000368166.5
DVL1	ENST00000378891	c.1990_*7delACATCATGTGACTCGTGG		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000368169.5

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Robinow syndrome 1 Uncertain:1

Sep 23, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PM4. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1643562079; hg19: chr1-1271514;