rs1085307143

Positions:

• chr16-51141112-GAC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002968.3(SALL1):​c.1108_1109delGT​(p.Val370fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL1 NM_002968.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-51141112-GAC-G is Pathogenic according to our data. Variant chr16-51141112-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 426114.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL1	NM_002968.3	c.1108_1109delGT	p.Val370fs	frameshift_variant	2/3	ENST00000251020.9	NP_002959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL1	ENST00000251020.9	c.1108_1109delGT	p.Val370fs	frameshift_variant	2/3	1	NM_002968.3	ENSP00000251020.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Townes-Brocks syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Apr 26, 2017

The following ACMG criteria are met: PVS1 (Predicted null variant in gene with LOF mechanism of disease), PM2 (Absent from population databases), PP4 (Patient's phenotype is specific for gene). The patient's clinical presentation is consistent with Townes-Brockes syndrome (anal stenosis, dysplastic ears, autism, developmental delays, sleep disturbance). A renal ultrasound found small kidneys with punctate echogenic foci bilaterally, and nephrology diagnosed him with chronic kidney disease stage 3. He had a normal cardiology evaluation. Brain MRI showed delayed myelination. His mother, who carries this variant, required speech therapy as a child. She has a history of kidney stones, but had normal renal ultrasound and cardiology evaluations. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1085307143; hg19: chr16-51175023;