rs1555850961

Positions:

• chr20-51791919-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000217086.9(SALL4):​c.563del​(p.Gly188AlafsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SALL4 ENST00000217086.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.90

Genes affected

SALL4 (HGNC:15924): (spalt like transcription factor 4) This gene encodes a zinc finger transcription factor thought to play a role in the development of abducens motor neurons. Defects in this gene are a cause of Duane-radial ray syndrome (DRRS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-51791919-GC-G is Pathogenic according to our data. Variant chr20-51791919-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 463530.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL4	NM_020436.5	c.563del	p.Gly188AlafsTer6	frameshift_variant	2/4	ENST00000217086.9	NP_065169.1
SALL4	NM_001318031.2	c.563del	p.Gly188AlafsTer6	frameshift_variant	2/4		NP_001304960.1
SALL4	XM_047440318.1	c.257del	p.Gly86AlafsTer6	frameshift_variant	2/4		XP_047296274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL4	ENST00000217086.9	c.563del	p.Gly188AlafsTer6	frameshift_variant	2/4	1	NM_020436.5	ENSP00000217086	P1
SALL4	ENST00000395997.3	c.563del	p.Gly188AlafsTer6	frameshift_variant	2/4	1		ENSP00000379319
SALL4	ENST00000371539.7	c.131-2779del		intron_variant		1		ENSP00000360594

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duane-radial ray syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2017

This sequence change deletes 1 nucleotide from exon 2 of the SALL4 mRNA (c.563delG), causing a frameshift at codon 188. This creates a premature translational stop signal (p.Gly188Alafs*6) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in SALL4 are known to be pathogenic (PMID: 12789647). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555850961; hg19: chr20-50408458;