rs74315425
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_020436.5(SALL4):c.2593C>T(p.Arg865Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SALL4
NM_020436.5 stop_gained
NM_020436.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 6.47
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-51789010-G-A is Pathogenic according to our data. Variant chr20-51789010-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SALL4 | NM_020436.5 | c.2593C>T | p.Arg865Ter | stop_gained | 3/4 | ENST00000217086.9 | |
SALL4 | NM_001318031.2 | c.1282C>T | p.Arg428Ter | stop_gained | 3/4 | ||
SALL4 | XM_047440318.1 | c.2287C>T | p.Arg763Ter | stop_gained | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SALL4 | ENST00000217086.9 | c.2593C>T | p.Arg865Ter | stop_gained | 3/4 | 1 | NM_020436.5 | P1 | |
SALL4 | ENST00000395997.3 | c.1282C>T | p.Arg428Ter | stop_gained | 3/4 | 1 | |||
SALL4 | ENST00000371539.7 | c.262C>T | p.Arg88Ter | stop_gained | 2/3 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1461884
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Cov.:
32
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0
AN XY:
727242
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Duane-radial ray syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2022 | This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg865*) in the SALL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SALL4 are known to be pathogenic (PMID: 15342710, 16086360). This premature translational stop signal has been observed in individual(s) with Duane-radial ray syndrome (PMID: 12395297). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3322). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2002 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2019 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 843249, 20301547, 12395297, 25525159, 11826030, 12843316) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at