16-51141744-CGCTGCTGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Position:

• chr16-51141744-CGCTGCTGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002968.3(SALL1):​c.477_478insAGCAGCAGCAGC​(p.Ser156_Ser159dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,580,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SALL1 NM_002968.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.34

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 16-51141744-C-CGCTGCTGCTGCT is Benign according to our data. Variant chr16-51141744-C-CGCTGCTGCTGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 591869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000113 (17/151110) while in subpopulation SAS AF= 0.00232 (11/4736). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL1	NM_002968.3	c.477_478insAGCAGCAGCAGC	p.Ser156_Ser159dup	inframe_insertion	2/3	ENST00000251020.9	NP_002959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SALL1	ENST00000251020.9	c.477_478insAGCAGCAGCAGC	p.Ser156_Ser159dup	inframe_insertion	2/3	1	NM_002968.3	ENSP00000251020	P2

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 151000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000206 AC: 295 AN: 1428918 Hom.: 0 Cov.: 43 AF XY: 0.000293 AC XY: 208 AN XY: 710692

Gnomad4 AFR exome AF: 0.000183

Gnomad4 AMR exome AF: 0.000161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00307

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000919

Gnomad4 OTH exome AF: 0.000187

GnomAD4 genome AF: 0.000113 AC: 17 AN: 151110 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 73820

Gnomad4 AFR AF: 0.0000972

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00232

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 06, 2020	- -

SALL1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2024

The SALL1 c.466_477dup12 variant is predicted to result in an in-frame duplication (p.Ser156_Ser159dup). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Townes syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2023

This variant has not been reported in the literature in individuals affected with SALL1-related conditions. This variant, c.466_477dup, results in the insertion of 4 amino acid(s) of the SALL1 protein (p.Ser156_Ser159dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 591869). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113614842; hg19: chr16-51175655;