NM_002968.3:c.3414_3415delAT
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_002968.3(SALL1):c.3414_3415delAT(p.Cys1139TrpfsTer35) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_002968.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461892Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Townes-Brocks syndrome 1 Pathogenic:3
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SALL1-related disorder Pathogenic:1
The SALL1 c.3414_3415delAT variant is predicted to result in a frameshift and premature protein termination (p.Cys1139Trpfs*35). This variant has previously been reported to be causative for renal hypodysplasia and Townes-Brocks Syndrome (Weber et al. 2006. PubMed: 16971658; Lawrence et al. 2013. PubMed: 23894113). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted by multiple laboratories in ClinVar as pathogenic (ClinVar ID 418466). Frameshift variants in SALL1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Townes syndrome Pathogenic:1
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys1139Trpfs*35) in the SALL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 186 amino acid(s) of the SALL1 protein. This premature translational stop signal has been observed in individual(s) with renal hypoplasia, congenital limb malformation, and Townes-Brocks syndrome (PMID: 16971658, 17221874, 18000979, 19429598, 23894113). 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: 418466). -
not provided Pathogenic:1
Frameshift variant predicted to result in abnormal protein length as the last 186 amino acids are replaced with 34 different amino acids, and other similar variants have been reported in HGMD; Published functional studies demonstrate reduced levels of cDNA in fibroblasts as compared to wild type but similar levels when treated with an inhibitor of nonsense-mediated mRNA decay (NMD), suggesting that the variant transcript undergoes NMD (PMID: 18000979); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23894113, 16971658, 18000979, 17221874) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at