NM_002968.3:c.2356delC

Variant names:

• chr16-51139865-CG-C
• rs1555475106
• NM_002968.3:c.2356delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002968.3(SALL1):​c.2356delC​(p.Arg786GlufsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R786R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL1 NM_002968.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.09
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 16-51139865-CG-C is Pathogenic according to our data. Variant chr16-51139865-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 528881.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002968.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL1	NM_002968.3	MANE Select	c.2356delC	p.Arg786GlufsTer36	frameshift	Exon 2 of 3	NP_002959.2
	SALL1	NM_001127892.2		c.2065delC	p.Arg689GlufsTer36	frameshift	Exon 2 of 3	NP_001121364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SALL1	ENST00000251020.9	TSL:1 MANE Select	c.2356delC	p.Arg786GlufsTer36	frameshift	Exon 2 of 3	ENSP00000251020.4
	SALL1	ENST00000566102.1	TSL:1	c.77-2314delC		intron	N/A	ENSP00000455582.1
	SALL1	ENST00000440970.6	TSL:5	c.2356delC	p.Arg786GlufsTer36	frameshift	Exon 3 of 4	ENSP00000407914.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Townes syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555475106; hg19: chr16-51173776;