16-51141744-C-CGCCGCT

Position:

• chr16-51141744-C-CGCCGCT

Variant summary

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

The NM_002968.3(SALL1):​c.477_478insAGCGGC​(p.Ser159_Gly160insSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,580,026 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 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SALL1 NM_002968.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• 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-CGCCGCT is Benign according to our data. Variant chr16-51141744-C-CGCCGCT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282759.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00116 (175/151110) while in subpopulation AFR AF= 0.00418 (172/41142). AF 95% confidence interval is 0.00367. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SALL1	NM_002968.3	c.477_478insAGCGGC	p.Ser159_Gly160insSerGly	conservative_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_478insAGCGGC	p.Ser159_Gly160insSerGly	conservative_inframe_insertion	2/3	1	NM_002968.3	ENSP00000251020.4

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 175 AN: 151000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD4 exome AF: 0.000147 AC: 210 AN: 1428916 Hom.: 0 Cov.: 43 AF XY: 0.000138 AC XY: 98 AN XY: 710692

Gnomad4 AFR exome AF: 0.00443

Gnomad4 AMR exome AF: 0.000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000441

Gnomad4 SAS exome AF: 0.0000833

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000919

Gnomad4 OTH exome AF: 0.000357

GnomAD4 genome AF: 0.00116 AC: 175 AN: 151110 Hom.: 0 Cov.: 31 AF XY: 0.00112 AC XY: 83 AN XY: 73820

Gnomad4 AFR AF: 0.00418

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SALL1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	Has not been previously published as pathogenic or benign to our knowledge -

Townes syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This variant, c.477_478insAGCGGC, results in the insertion of 2 amino acid(s) of the SALL1 protein (p.Ser159_Gly160insSerGly), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SALL1-related conditions. This variant has been observed in at least one individual who was not affected with SALL1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 282759). 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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 02, 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: rs1555475415; hg19: chr16-51175655;