16-51141356-A-T

Variant names:

• chr16-51141356-A-T
• rs1555475334
• NM_002968.3:c.866T>A

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.866T>A​(p.Leu289*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SALL1 NM_002968.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.55

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 16-51141356-A-T is Pathogenic according to our data. Variant chr16-51141356-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 528879.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SALL1	NM_002968.3	c.866T>A	p.Leu289*	stop_gained	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	c.866T>A	p.Leu289*	stop_gained	Exon 2 of 3	1	NM_002968.3	ENSP00000251020.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 53

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Townes syndrome Pathogenic:1

Dec 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in a truncated protein lacking all DZF domains which are critical for SALL1 protein function. This variant has not been reported in the literature in individuals with a SALL1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SALL1 gene (p.Leu289*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 1036 amino acids (~78%) of the SALL1 protein. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.82
GERP RS		4.8

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: rs1555475334; hg19: chr16-51175267;