rs864321635

Positions:

• chr16-51139062-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_002968.3(SALL1):​c.3160C>T​(p.Arg1054Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL1 NM_002968.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 3.76

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 Pathogenic. Variant got 14 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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-51139062-G-A is Pathogenic according to our data. Variant chr16-51139062-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL1	NM_002968.3	c.3160C>T	p.Arg1054Ter	stop_gained	2/3	ENST00000251020.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL1	ENST00000251020.9	c.3160C>T	p.Arg1054Ter	stop_gained	2/3	1	NM_002968.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Townes syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This sequence change creates a premature translational stop signal (p.Arg1054*) in the SALL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 271 amino acid(s) of the SALL1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been reported to segregate with multiple congenital anomaly-intellectual disability in a family (PMID: 23069192). In this family, two affected siblings were homozygous for this variant. Eleven heterozygous carriers from this family were clinically evaluated with emphasis on minor Townes-Brocks syndrome (TBS) features, and were all found to be unaffected. Another heterozygous carrier, who was not available for thorough clinical evaluation, was also reported to be healthy. However, this variant has also been observed in different families, where the heterozygous probands and heterozygous family members had clinical features consistent with TBS (Invitae). ClinVar contains an entry for this variant (Variation ID: 219151). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2022

Reported in the homozygous state in two individuals from the same family with multiple congenital anomalies including imperforate anus and triphalangeal thumbs in published literature (Vodopiutz et al., 2013); parents are noted to be heterozygous and unaffected; 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: 26962299, 23069192) -

Townes-Brocks syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;D;D
Vest4		0.94
GERP RS		5.6

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: rs864321635; hg19: chr16-51172973; COSMIC: COSV51759482; COSMIC: COSV51759482;