NM_002968.3:c.3414_3415delAT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SALL1
NM_002968.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.31

Publications

4 publications found

Variant links:

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]

SALL1 Gene-Disease associations (from GenCC):

Townes-Brocks syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Townes-Brocks syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SALL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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;

PP5

Variant 16-51138806-CAT-C is Pathogenic according to our data. Variant chr16-51138806-CAT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 418466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL1	NM_002968.3 link	c.3414_3415delAT	p.Cys1139TrpfsTer35	frameshift_variant	Exon 2 of 3	ENST00000251020.9	NP_002959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SALL1	ENST00000251020.9 link	c.3414_3415delAT	p.Cys1139TrpfsTer35	frameshift_variant	Exon 2 of 3	1	NM_002968.3	ENSP00000251020.4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Townes-Brocks syndrome 1

Pathogenic:3

Dec 15, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 05, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SALL1-related disorder

Pathogenic:1

Apr 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jul 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Inborn genetic diseases

Pathogenic:1

Mar 07, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3414_3415delAT (p.C1139Wfs*35) alteration, located in exon 2 (coding exon 2) of the SALL1 gene, consists of a deletion of 2 nucleotides from position 3414 to 3415, causing a translational frameshift with a predicted alternate stop codon after 35 amino acids. This variant is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 14% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple unrelated individuals with features consistent with SALL1-related Townes-Brocks syndrome (Weber, 2006; Furniss, 2007) and segregated with disease in at least one family (Botzenhart, 2007; Lawrence, 2013). Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Oct 16, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.3

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over