rs104894537
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002968.3(SALL1):c.826C>T(p.Arg276Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SALL1
NM_002968.3 stop_gained
NM_002968.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.83
Genes affected
SALL1 (HGNC:10524): (spalt like transcription factor 1) The protein encoded by this gene is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase complex (HDAC). Defects in this gene are a cause of Townes-Brocks syndrome (TBS) as well as bronchio-oto-renal syndrome (BOR). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 42 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-51141396-G-A is Pathogenic according to our data. Variant chr16-51141396-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-51141396-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SALL1 | NM_002968.3 | c.826C>T | p.Arg276Ter | stop_gained | 2/3 | ENST00000251020.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SALL1 | ENST00000251020.9 | c.826C>T | p.Arg276Ter | stop_gained | 2/3 | 1 | NM_002968.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461682Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0AN XY: 727146
GnomAD4 exome
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1
AN:
1461682
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52
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0
AN XY:
727146
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Townes-Brocks syndrome 1 Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 31, 2023 | PVS1, PS4, PM2, PM6_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Apr 17, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2001 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 31, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Feb 01, 2022 | - - |
Townes syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Jan 17, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2023 | ClinVar contains an entry for this variant (Variation ID: 7428). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with clinical features of Townes-Brocks syndrome (PMID: 9973281, 10533063, 19005989). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg276*) in the SALL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SALL1 are known to be pathogenic (PMID: 9973281, 12915476, 16088922, 23069192). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18470945, 9425907, 16892410, 25525159, 29395072, 28973083, 14627694, 10533063, 11102974, 30655312, 32359821, 31328266, 9973281) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;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