20-51791986-TG-TGG

Variant summary

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

The NM_020436.5(SALL4):c.496_497insC(p.Gln166ProfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SALL4 NM_020436.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL4	NM_020436.5	c.496_497insC	p.Gln166ProfsTer15	frameshift_variant	2/4	ENST00000217086.9
SALL4	NM_001318031.2	c.496_497insC	p.Gln166ProfsTer15	frameshift_variant	2/4
SALL4	XM_047440318.1	c.190_191insC	p.Gln64ProfsTer15	frameshift_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL4	ENST00000217086.9	c.496_497insC	p.Gln166ProfsTer15	frameshift_variant	2/4	1	NM_020436.5	P1
SALL4	ENST00000395997.3	c.496_497insC	p.Gln166ProfsTer15	frameshift_variant	2/4	1
SALL4	ENST00000371539.7	c.131-2846_131-2845insC		intron_variant		1
SALL4	ENST00000483130.1	n.778_779insC		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044509; hg19: chr20-50408525;