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. Fraction of 0.18 CDS is truncated, and there are 1 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SALL4 | NM_020436.5 | c.2593C>T | p.Arg865Ter | stop_gained | 3/4 | ENST00000217086.9 | NP_065169.1 | |
SALL4 | NM_001318031.2 | c.1282C>T | p.Arg428Ter | stop_gained | 3/4 | NP_001304960.1 | ||
SALL4 | XM_047440318.1 | c.2287C>T | p.Arg763Ter | stop_gained | 3/4 | XP_047296274.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SALL4 | ENST00000217086.9 | c.2593C>T | p.Arg865Ter | stop_gained | 3/4 | 1 | NM_020436.5 | ENSP00000217086 | P1 | |
SALL4 | ENST00000395997.3 | c.1282C>T | p.Arg428Ter | stop_gained | 3/4 | 1 | ENSP00000379319 | |||
SALL4 | ENST00000371539.7 | c.262C>T | p.Arg88Ter | stop_gained | 2/3 | 1 | ENSP00000360594 |
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
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0
AN:
1461884
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32
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0
AN XY:
727242
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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 | Labcorp Genetics (formerly Invitae), Labcorp | 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
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at