rs104894537

Positions:

• chr16-51141396-G-A
• chr16-51141396-G-T

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.826C>T​(p.Arg276*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SALL1 NM_002968.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.83

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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-51141396-G-A is Pathogenic according to our data. Variant chr16-51141396-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-51141396-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL1	NM_002968.3	c.826C>T	p.Arg276*	stop_gained	2/3	ENST00000251020.9	NP_002959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL1	ENST00000251020.9	c.826C>T	p.Arg276*	stop_gained	2/3	1	NM_002968.3	ENSP00000251020.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461682 Hom.: 0 Cov.: 52 AF XY: 0.00 AC XY: 0 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Townes-Brocks syndrome 1 Pathogenic:7 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 31, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 31, 2023	PVS1, PS4, PM2, PM6_Strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	Precision Medicine Center, Zhengzhou University	Dec 01, 2023	PS2,PM2_p,PP3 -

Townes syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Jan 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	ClinVar contains an entry for this variant (Variation ID: 7428). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with clinical features of Townes-Brocks syndrome (PMID: 9973281, 10533063, 19005989). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg276*) in the SALL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SALL1 are known to be pathogenic (PMID: 9973281, 12915476, 16088922, 23069192). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2023

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: 18470945, 9425907, 16892410, 25525159, 29395072, 28973083, 14627694, 10533063, 11102974, 30655312, 32359821, 31328266, 9973281) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.80
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: rs104894537; hg19: chr16-51175307; COSMIC: COSV51753567; COSMIC: COSV51753567;